rs121918221

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_006363.6(SEC23B):c.325G>A(p.Glu109Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,612,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SEC23B
NM_006363.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 9.83

Publications

34 publications found

Variant links:

Genes affected

SEC23B (HGNC:10702): (SEC23 homolog B, COPII coat complex component) The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The function of this gene product has been implicated in cargo selection and concentration. Multiple alternatively spliced transcript variants have been identified in this gene. [provided by RefSeq, Feb 2010]

SEC23B Gene-Disease associations (from GenCC):

congenital dyserythropoietic anemia type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, G2P
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 7
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
congenital dyserythropoietic anemia
Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

SEC23B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 20-18515695-G-A is Pathogenic according to our data. Variant chr20-18515695-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC23B	NM_006363.6 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 4 of 20	ENST00000650089.1	NP_006354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC23B	ENST00000650089.1 link	c.325G>A	p.Glu109Lys	missense_variant	Exon 4 of 20		NM_006363.6	ENSP00000497473.1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000227

AC:

AN:

251456

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000268

AC:

391

AN:

1459918

Hom.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

726452

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33446

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000332

AC:

369

AN:

1110212

Other (OTH)

AF:

0.000182

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000243

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68008

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000401

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital dyserythropoietic anemia, type II

Pathogenic:9

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 22, 2021

Institute of Human Genetics, Heidelberg University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 05, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SEC23B c.325G>A (p.Glu109Lys) variant has been reported in at least three studies and is found in a total of 25 individuals including 23 in a homozygous state and two in a compound heterozygous state with congenital dyserythropoietic anemia (Schwarz et al. 2009; Bianchi et al. 2009; Punzo et al. 2011; Amir et al. 2011). The p.Glu109Lys variant is described as a founder mutation among the Israeli Moroccan Jewish population (Amir et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.000577 in the African population of the Exome Aggregation Consortium. Expression analysis in HeLa-Kyoto cells determined the p.Glu109Lys variant had less than 5% of wildtype expression (Schwarz et al. 2009). Based on the evidence, the p.Glu109Lys variant is classified as pathogenic for congenital dyserythropoietic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jun 13, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2025

BloodGenetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_006363.6(SEC23B): c.325G>A (p.Glu109Lys) missense variant replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 109 of the SEC23B protein (p.Glu109Lys). This variant (rs121918221) is reported in the literature in multiple individuals affected with congenital dyserythropoietic anemia (CDA) type II (PMID: 19561605, 19621418, 20015893, 21252497, 21850656, 25044164). This variant is reported as pathogenic by multiple laboratories in ClinVar (VCV.version: VCV000001222.65). This variant is present in population databases (rs121918221, gnomAD 0.04%). We found this variant in compound heterozygosity or homozygosity in 4 individuals affected by CDA type II: Case60-Patient114 (Family 1); Case82U-patient159U (Family 3); Case00388-P-00210 (Family 6); Case00429-P-00249 (Family 8). All these cases are published in paper PMID: 37373084 where functional studies for this variant and other variants were done. In summary, this variant meets criteria to be classified as pathogenic for CDA type II based on the ACMG/AMP criteria applied: PM2strong, PP5strong, PS3strong, PP3supporting. -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS1,PM3,PP3,PP4,PP5. -

Jun 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SEC23B c.325G>A (p.Glu109Lys) results in a conservative amino acid change to a well-conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251456 control chromosomes in the gnomAD database, including 1 homozygote. c.325G>A has been reported in the literature in multiple individuals affected with Congenital dyserythropoietic anemia, type II (Schwarz_2009, Russo_2011), and at least one was reported as compound heterozygous with a (likely) pathogenic variant. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein stability, finding less than 5% of protein detectable compared to wild-type SEC23B. The following publications have been ascertained in the context of this evaluation (PMID: 19561605, 21850656). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital dyserythropoietic anemia, type II (MIM#224100). (I) 0106 - This gene is known to be associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to a lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 59 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is very highly conserved with a minor amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as compound heterozygous or homozygous in multiple individuals with congenital dyserythropoietic anaemia and classified as pathogenic by clinical diagnostic laboratories (ClinVar; PMIDs: 21252497, 32641076, 34093240). Moreover, this variant has also been described as a Moroccon Jewish founder mutation (PMID: 21252497). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:7

Jul 31, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SEC23B: PM3:Very Strong, PM2, PS3:Supporting -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2013

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3 -

Dec 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SEC23B c.325G>A; p.Glu109Lys variant (rs121918221) is reported in the literature in both homozygous and compound heterozygous states in individuals with congenital dyserythropoietic anemia, type II (Amir 2011, Iolascon 2010, Russo 2018, Russo 2011, Schwarz 2009, Wright 2019). This particular SEC23B variant is considered a founder mutation in both Italian and Moroccan-Jewish populations (Amir 2011, Russo 2011). Functional studies demonstrate that this variant results in reduced SEC23B expression and protein mislocalization (Schwarz 2009, Wei 2022). This variant is reported as pathogenic in ClinVar (Variation ID: 1222). This variant is found in the general population with an overall allele frequency of 0.02% (61/282848 alleles, including one homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.948). Based on available information, this variant is considered to be pathogenic. References: Amir A et al. E109K is a SEC23B founder mutation among Israeli Moroccan Jewish patients with congenital dyserythropoietic anemia type II. Acta Haematol. 2011 PMID: 21252497. Iolascon A et al. Molecular analysis of 42 patients with congenital dyserythropoietic anemia type II: new mutations in the SEC23B gene and a search for a genotype-phenotype relationship. Haematologica. 2010 May. PMID: 20015893. Russo R et al. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. Am J Hematol. 2018 May. PMID: 29396846. Russo R et al. Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population. Am J Hematol. 2011 Sep. PMID: 21850656 .Schwarz K et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nature genetics. 2009 Aug. PMID: 19561605. Wei W et al. A common human missense mutation of vesicle coat protein SEC23B leads to growth restriction and chronic pancreatitis in mice. J Biol Chem. 2022 Jan. PMID: 34954140. Wright CF et al. Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting. Am J Hum Genet. 2019 Feb 7. PMID: 30665703 -

Mar 30, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7

Pathogenic:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 109 of the SEC23B protein (p.Glu109Lys). This variant is present in population databases (rs121918221, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with congenital dyserythropoietic anemia type II (PMID: 19561605, 19621418, 20015893, 21252497, 21850656, 25044164). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1222). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SEC23B protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SEC23B function (PMID: 19561605). For these reasons, this variant has been classified as Pathogenic. -

Mar 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SEC23B-related disorder

Pathogenic:1

Feb 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SEC23B c.325G>A variant is predicted to result in the amino acid substitution p.Glu109Lys. This variant has been reported as causative for autosomal recessive dyserythropoietic anemia type II (Schwarz et al. 2009. PubMed ID: 19561605; Fermo et al. 2010. PubMed ID: 20381388; Amir et al. 2011. PubMed ID: 21252497; Russo et al. 2011. PubMed ID: 21850656). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

See cases

Pathogenic:1

Oct 11, 2024

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PS3,PS4,PM2_sup,PM3_strong,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.42

T;T;T;T;.;T;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;D;.;D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;H;.;H;.;H;H

PhyloP100

9.8

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.6

D;D;D;D;.;.;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D;D;.;.;D

Sift4G

Uncertain

0.0030

D;D;D;D;.;.;D

Polyphen

1.0

D;D;.;D;.;D;D

Vest4

0.98

MVP

0.98

MPC

0.73

ClinPred

0.93

GERP RS

5.0

Varity_R

0.81

gMVP

0.90

Mutation Taster

=43/57

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over