rs727504145

Positions:

chr20-18542380-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_006363.6(SEC23B):c.1489C>T(p.Arg497Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,086 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SEC23B
NM_006363.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.94

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 20-18542380-C-T is Pathogenic according to our data. Variant chr20-18542380-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 167667.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 linkuse as main transcript	c.1489C>T	p.Arg497Cys	missense_variant	13/20	ENST00000650089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23B	ENST00000650089.1 linkuse as main transcript	c.1489C>T	p.Arg497Cys	missense_variant	13/20		NM_006363.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251434

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2023	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 497 of the SEC23B protein (p.Arg497Cys). This variant is present in population databases (rs727504145, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type II (PMID: 19561605, 19621418, 20015893, 27471141). ClinVar contains an entry for this variant (Variation ID: 167667). 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. For these reasons, this variant has been classified as Pathogenic. -

Congenital dyserythropoietic anemia, type II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 31, 2018

The SEC23B c.1489C>T (p.Arg497Cys) variant has been reported in five studies and in a total of nine individuals with dyserythropoietic anemia including one individual in a homozygous state and eight individuals in a compound heterozygous state (Schwarz et al. 2009, Bianchi et al. 2009, Iolascon et al. 2010, Russo et al. 2010, Russo et al. 2013). The variant was absent from 407 controls and is reported at a frequency of 0.000032 in the European (non-Finnish) population of the Genome Aggregation Database. The Arg497 amino acid residue is conserved among several species. Based on the evidence, the p.Arg497Cys 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;T;T;.;T;T;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.4

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

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98

MVP

0.97

MPC

0.81

ClinPred

1.0

GERP RS

4.8

Varity_R

0.93

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over