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GeneBe

rs13181

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_ModeratePM2_Supporting

The NM_000400.4(ERCC2):c.2251A>T(p.Lys751Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★). Synonymous variant affecting the same amino acid position (i.e. K751K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 stop_gained

Scores

2
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Links

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Fraction of 0.014 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ERCC2NM_000400.4 linkuse as main transcriptc.2251A>T p.Lys751Ter stop_gained 23/23 ENST00000391945.10
ERCC2XM_011526611.3 linkuse as main transcriptc.2173A>T p.Lys725Ter stop_gained 22/22
ERCC2XR_001753633.3 linkuse as main transcriptn.2284A>T non_coding_transcript_exon_variant 23/24
ERCC2XR_007066680.1 linkuse as main transcriptn.2206A>T non_coding_transcript_exon_variant 22/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERCC2ENST00000391945.10 linkuse as main transcriptc.2251A>T p.Lys751Ter stop_gained 23/231 NM_000400.4 P1P18074-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250340
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135454
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461724
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727146
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

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 testingInvitaeDec 09, 2021This sequence change creates a premature translational stop signal (p.Lys751*) in the ERCC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the ERCC2 protein. This variant is present in population databases (rs13181, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
43
Dann
Uncertain
0.99
Eigen
Uncertain
0.28
Eigen_PC
Benign
0.073
FATHMM_MKL
Uncertain
0.86
D
MutationTaster
Benign
1.0
D;D
Vest4
0.62
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs13181; hg19: chr19-45854919; API