NM_000082.4:c.1183G>C

Variant names:

• chr5-60874623-C-G
• NM_000082.4:c.1183G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000082.4(ERCC8):​c.1183G>C​(p.Glu395Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,290 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ERCC8 NM_000082.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17104408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.1183G>C	p.Glu395Gln	missense_variant	Exon 12 of 12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.1009G>C	p.Glu337Gln	missense_variant	Exon 13 of 13		NP_001007234.1
ERCC8	NM_001290285.2	c.724G>C	p.Glu242Gln	missense_variant	Exon 11 of 11		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.1183G>C	p.Glu395Gln	missense_variant	Exon 12 of 12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461290 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726934

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.090
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.035	D
Polyphen		0.079	B
Vest4		0.21
MutPred		0.30		Loss of glycosylation at S391 (P = 0.1872);
MVP		0.82
MPC		0.19
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-60170450;