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rs1799793

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

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.64

Links

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
ERCC2NM_000400.4 linkuse as main transcriptc.934G>T p.Asp312Tyr missense_variant 10/23 ENST00000391945.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERCC2ENST00000391945.10 linkuse as main transcriptc.934G>T p.Asp312Tyr missense_variant 10/231 NM_000400.4 P1P18074-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000707
AC:
1
AN:
141480
Hom.:
0
AF XY:
0.0000130
AC XY:
1
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:
2
AN:
1391598
Hom.:
0
AF XY:
0.00000291
AC XY:
2
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 submitterclinical testingInvitaeJan 15, 2022This 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
D
BayesDel_noAF
Pathogenic
0.26
Cadd
Uncertain
25
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
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Uncertain
2.8
M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.79
T
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
D
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.

Other links and lift over

dbSNP: rs1799793; hg19: chr19-45867259;