20-18510875-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_006363.6(SEC23B):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,968 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SEC23B NM_006363.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.06

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 20-18510875-C-T is Pathogenic according to our data. Variant chr20-18510875-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC23B	NM_006363.6	c.40C>T	p.Arg14Trp	missense_variant	2/20	ENST00000650089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23B	ENST00000650089.1	c.40C>T	p.Arg14Trp	missense_variant	2/20		NM_006363.6	P1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251450 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74274

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2020	PS3, PS4_moderate, PM3, PP1, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SEC23B p.R14W variant was identified in 36 of 178 proband chromosomes (frequency: 0.202; 1 homozygote, 3 heterozygotes, and 31 compound heterozygotes) from individuals or families with Congenital Dyserythropoietic Anemia type II (CDAII) (Punzo_2011_PMID:22208203; Russo_2011_PMID:21850656; Iolascon_2010_PMID:20015893; Bianchi_2009_PMID:19621418). A case report of an 18 year-old boy with chronic mild congenital anemia of unknown origin, chronic jaundice, and splenomegaly caused by non-autoimmune hemolytic anemia since 18 months of age was found to have two causative mutations in the SEC23B gene: the p.R14W variant and a novel frameshift deletion p.V164Wfs*3; the patient’s non-consanguineous parents with no history of anemia were heterozygous for either mutation (Koker_2018_PMID:29846281). The variant was identified in dbSNP (ID: rs121918222) and ClinVar (classified as pathogenic by Invitae, GeneDx and EGL Genetic Diagnostics for congenital dyserythropoietic anemia, type II). The variant was identified in control databases in 67 of 282848 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 21 of 35440 chromosomes (freq: 0.000593), Other in 4 of 7224 chromosomes (freq: 0.000554), European (non-Finnish) in 32 of 129154 chromosomes (freq: 0.000248), Ashkenazi Jewish in 2 of 10368 chromosomes (freq: 0.000193), East Asian in 3 of 19954 chromosomes (freq: 0.00015), South Asian in 3 of 30616 chromosomes (freq: 0.000098), African in 1 of 24972 chromosomes (freq: 0.00004), and European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg14 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies demonstrated that the p.R14W variant resulted in <5% of detectable protein compared to wildtype, however the p.R14W variant was coimmunoprecipitated by SEC24D simlarly to wildtype (Schwarz_2009_PMID:19561605). In addition, Satchwell et al. conducted in vitro studies to track the appearance of the CDAII phenotype during erythroblast differentiation in 5 unrelated patients, 3 of whom were compound heterozygotes for the p.R14W variant; patient erythroblasts displayed the characteristic CDAII phenotype including multinuclearity, erythrocyte membrane protein hypoglycosylation, and residual endoplasmic reticulum (Satchwell_2013_PMID:23935019). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2022	One of the most common recurrent variants in the SEC23B gene and is considered a founder mutation in Italy, Morocco, and Israel (Russo et al., 2014); Published functional studies demonstrate a damaging effect: in vitro studies indicate the variant is unstable with less than 5% of the protein detectable compared to wild type (Schwarz et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21850656, 23935019, 19621418, 29846281, 20015893, 22208203, 33159567, 19561605, 25044164, 34426522, 31589614, 32641076) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SEC23B: PS3:Very Strong, PS4, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2022	The SEC23B c.40C>T; p.Arg14Trp variant (rs121918222) has been reported in the literature as a founder mutation associated with congenital dyserythropoietic anemia type II (CDA II) in the Italian population (Russo 2011). In CDA II patients, the p.Arg14Trp variant was always detected along with an additional SEC23B pathogenic variant as a compound heterozygote (Aydin Koker 2018, Bianchi 2009, Iolascon 2010, Mansour-Hendili 2020, Mendez 2021, Moreno-Carralero 2018, Punzo 2011, Schwarz 2009). This SEC23B variant is reported as pathogenic in ClinVar (Variation ID: 1223). This variant is found in the general population with an overall allele frequency of 0.02% (67/282848 alleles) in the Genome Aggregation Database. The arginine at codon 14 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.75). In addition, in vitro functional analyses demonstrate that Arg14Trp-mutated SEC23B is extremely unstable with less than 5% of residual protein activity (Schwarz 2009). Based on available information, this SEC23B variant is considered to be pathogenic. -

Congenital dyserythropoietic anemia, type II Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Mar 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, 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 associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (67 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes) (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a compound heterozygous state with another pathogenic variant in multiple individuals (ClinVar, PMID: 19621418, 19561605, 25044164). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001494). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the SEC23B protein (p.Arg14Trp). This variant is present in population databases (rs121918222, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type II (PMID: 19561605, 19621418, 20015893, 21850656). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1223). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SEC23B protein function. Experimental studies have shown that this missense change affects SEC23B function (PMID: 19561605). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;.;T;T;.;.;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;M;.;.;.;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D;D;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.75
Sift	Benign	0.055	T;T;.;D;T;.;.;.;.;T
Sift4G	Uncertain	0.018	D;D;.;D;D;.;.;.;.;D
Polyphen		1.0	D;D;.;.;D;.;.;.;D;D
Vest4		0.72
MVP		0.93
MPC		0.60
ClinPred		0.80	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs121918222; hg19: chr20-18491519; COSMIC: COSV104581253; COSMIC: COSV104581253;