10-49459232-A-T

Variant summary

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

The NM_000124.4(ERCC6):c.4065T>A(p.Asp1355Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1355V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC6 NM_000124.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.4065T>A	p.Asp1355Glu	missense_variant, splice_region_variant	21/21	ENST00000355832.10
ERCC6	NM_001346440.2	c.4065T>A	p.Asp1355Glu	missense_variant, splice_region_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.4065T>A	p.Asp1355Glu	missense_variant, splice_region_variant	21/21	1	NM_000124.4	P1
	ENST00000423283.1	n.235-13471A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	8.8
Dann	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.39
Sift	Benign	0.20	T
Sift4G	Benign	0.42	T
Polyphen		0.88	P
Vest4		0.18
MutPred		0.12		Gain of helix (P = 0.0425);
MVP		0.38
MPC		0.15
ClinPred		0.16	T
GERP RS		-11
Varity_R		0.047
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34917815; hg19: chr10-50667278;