5-60902446-C-G

Position:

• chr5-60902446-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000082.4(ERCC8):​c.613G>C​(p.Ala205Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,458,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ERCC8 NM_000082.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 5.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a strand (size 5) in uniprot entity ERCC8_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000082.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 5-60902446-C-G is Pathogenic according to our data. Variant chr5-60902446-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60902446-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.613G>C	p.Ala205Pro	missense_variant	7/12	ENST00000676185.1
ERCC8	NM_001007233.3	c.439G>C	p.Ala147Pro	missense_variant	8/13
ERCC8	NM_001290285.2	c.154G>C	p.Ala52Pro	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.613G>C	p.Ala205Pro	missense_variant	7/12		NM_000082.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000638 AC: 16 AN: 250866 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000464

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: 0.0000110 AC: 16 AN: 1458226 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 725542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000358

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 30, 2023	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 205 of the ERCC8 protein (p.Ala205Pro). This variant is present in population databases (rs121434326, gnomAD 0.05%). This missense change has been observed in individual(s) with Cockayne syndrome (PMID: 14661080, 32048102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1718). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC8 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ERCC8 function (PMID: 16949367, 29531219). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	Published functional studies demonstrate a damaging effect (Pines et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17084038, 14661080, 23571135, 28333167, 16865293, 29531219, 25653723, 19894250, 32048102) -

Cockayne syndrome type 1 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	May 12, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.046	D
Polyphen		0.98	D
Vest4		0.85
MutPred		0.82		Loss of catalytic residue at A205 (P = 0.0221);
MVP		0.87
MPC		0.34
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.88

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

Other links and lift over

dbSNP: rs121434326; hg19: chr5-60198273;