19-45352262-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_000400.4(ERCC2):​c.2137G>A​(p.Gly713Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. G713A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23
Variant links:
Genes affected
ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000400.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-45352262-C-G is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.23413187).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC2NM_000400.4 linkc.2137G>A p.Gly713Ser missense_variant Exon 22 of 23 ENST00000391945.10 NP_000391.1 P18074-1
ERCC2XM_011526611.3 linkc.2059G>A p.Gly687Ser missense_variant Exon 21 of 22 XP_011524913.1
ERCC2XR_001753633.3 linkn.2170G>A non_coding_transcript_exon_variant Exon 22 of 24
ERCC2XR_007066680.1 linkn.2092G>A non_coding_transcript_exon_variant Exon 21 of 23

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC2ENST00000391945.10 linkc.2137G>A p.Gly713Ser missense_variant Exon 22 of 23 1 NM_000400.4 ENSP00000375809.4 P18074-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461798
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727194
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G713S variant (also known as c.2137G>A), located in coding exon 22 of the ERCC2 gene, results from a G to A substitution at nucleotide position 2137. The glycine at codon 713 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.031
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T;T;T
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.23
T;T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
-1.4
N;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
0.99
N;N;.
REVEL
Uncertain
0.36
Sift
Benign
0.088
T;T;.
Sift4G
Benign
0.13
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.28
MutPred
0.63
Loss of loop (P = 0.0804);.;.;
MVP
0.88
MPC
0.21
ClinPred
0.39
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.091
gMVP
0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45855520; COSMIC: COSV67270676; COSMIC: COSV67270676; API