chr5-60902454-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM2PP3_Strong

The NM_000082.4(ERCC8):​c.605T>C​(p.Leu202Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)

Consequence

ERCC8
NM_000082.4 missense

Scores

12
6
1

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 8.05
Variant links:
Genes affected
ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1
Transcript NM_000082.4 (ERCC8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC8NM_000082.4 linkuse as main transcriptc.605T>C p.Leu202Ser missense_variant 7/12 ENST00000676185.1 NP_000073.1 Q13216-1
ERCC8NM_001007233.3 linkuse as main transcriptc.431T>C p.Leu144Ser missense_variant 8/13 NP_001007234.1 B3KPW7
ERCC8NM_001290285.2 linkuse as main transcriptc.146T>C p.Leu49Ser missense_variant 6/11 NP_001277214.1 B3KPW7B4DGZ9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC8ENST00000676185.1 linkuse as main transcriptc.605T>C p.Leu202Ser missense_variant 7/12 NM_000082.4 ENSP00000501614.1 Q13216-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not provided Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.56
D
MutationAssessor
Pathogenic
4.6
H
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.2
D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.79
Gain of disorder (P = 0.0138);
MVP
0.94
MPC
0.40
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.99
gMVP
0.85

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: rs281875224; hg19: chr5-60198281; API