Variant rs1799793 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_SupportingPP3_Moderate

The NM_000400.4(ERCC2):c.934G>T(p.Asp312Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D312N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.64

Links

ERCC2 (HGNC:3434):

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant; Number of alleles below threshold, Median coverage is 33.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4 linkuse as main transcript	c.934G>T	p.Asp312Tyr	missense_variant	10/23	ENST00000391945.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.934G>T	p.Asp312Tyr	missense_variant	10/23	1	NM_000400.4	P1	P18074-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000707

AC:

AN:

141480

Hom.:

AF XY:

0.0000130

AC XY:

AN XY:

77124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1391598

Hom.:

AF XY:

0.00000291

AC XY:

AN XY:

686696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000279

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 312 of the ERCC2 protein (p.Asp312Tyr). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.26

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.8

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.2

D;D;.;D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

D;D;.;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

0.64

P;P;.;.;.

Vest4

0.72

MutPred

0.50

Loss of disorder (P = 0.0494);.;.;.;.;

MVP

0.85

MPC

0.87

ClinPred

0.98

GERP RS

5.2

Varity_R

0.95

gMVP

0.84

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over