20-18542358-C-G

Variant names:

• chr20-18542358-C-G
• rs2273526
• NM_006363.6:c.1467C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006363.6(SEC23B):​c.1467C>G​(p.His489Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,614,028 control chromosomes in the GnomAD database, including 11,624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1301 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10323 hom.)
• Consequence: SEC23B NM_006363.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0430
• Publications: 35 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026350617).
• BP6: Variant 20-18542358-C-G is Benign according to our data. Variant chr20-18542358-C-G is described in ClinVar as Benign. ClinVar VariationId is 95382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC23B	NM_006363.6	MANE Select	c.1467C>G	p.His489Gln	missense	Exon 13 of 20	NP_006354.2
	SEC23B	NM_001172745.3		c.1467C>G	p.His489Gln	missense	Exon 13 of 20	NP_001166216.1
	SEC23B	NM_032985.6		c.1467C>G	p.His489Gln	missense	Exon 13 of 20	NP_116780.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC23B	ENST00000650089.1	MANE Select	c.1467C>G	p.His489Gln	missense	Exon 13 of 20	ENSP00000497473.1
	SEC23B	ENST00000336714.8	TSL:1	c.1467C>G	p.His489Gln	missense	Exon 13 of 20	ENSP00000338844.3
	SEC23B	ENST00000377465.6	TSL:1	c.1467C>G	p.His489Gln	missense	Exon 13 of 20	ENSP00000366685.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19043 AN: 152160 Hom.: 1302 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0411

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.128 AC: 32275 AN: 251452 AF XY: 0.122

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.114 AC: 167281 AN: 1461750 Hom.: 10323 Cov.: 33 AF XY: 0.112 AC XY: 81585 AN XY: 727184

African (AFR) AF: 0.117 AC: 3911 AN: 33478

American (AMR) AF: 0.204 AC: 9131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3884 AN: 26136

East Asian (EAS) AF: 0.150 AC: 5942 AN: 39696

South Asian (SAS) AF: 0.0456 AC: 3936 AN: 86258

European-Finnish (FIN) AF: 0.128 AC: 6856 AN: 53408

Middle Eastern (MID) AF: 0.138 AC: 797 AN: 5766

European-Non Finnish (NFE) AF: 0.113 AC: 125910 AN: 1111894

Other (OTH) AF: 0.114 AC: 6914 AN: 60390

GnomAD4 genome AF: 0.125 AC: 19045 AN: 152278 Hom.: 1301 Cov.: 33 AF XY: 0.126 AC XY: 9368 AN XY: 74460

African (AFR) AF: 0.114 AC: 4741 AN: 41548

American (AMR) AF: 0.183 AC: 2801 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 574 AN: 3472

East Asian (EAS) AF: 0.160 AC: 830 AN: 5174

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4832

European-Finnish (FIN) AF: 0.131 AC: 1387 AN: 10612

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8015 AN: 68026

Other (OTH) AF: 0.144 AC: 304 AN: 2112

Alfa AF: 0.110 Hom.: 792

Bravo AF: 0.132

TwinsUK AF: 0.118 AC: 439

ALSPAC AF: 0.109 AC: 421

ESP6500AA AF: 0.121 AC: 531

ESP6500EA AF: 0.118 AC: 1012

ExAC AF: 0.124 AC: 15100

Asia WGS AF: 0.0990 AC: 344 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29300242, 29031773)

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 09, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital dyserythropoietic anemia, type II Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cowden syndrome 7 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.043
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.013	D
Polyphen		0.45	B
Vest4		0.24
MutPred		0.28		Gain of MoRF binding (P = 0.0941)
MPC		0.39
ClinPred		0.11	T
GERP RS		0.58
PromoterAI		-0.013	Neutral
Varity_R		0.84
gMVP		0.75
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2273526; hg19: chr20-18523002; COSMIC: COSV52719183; COSMIC: COSV52719183;