2-127259306-C-G

Variant names:

• chr2-127259306-C-G
• rs587778276
• NM_000122.2:c.2207G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000122.2(ERCC3):​c.2207G>C​(p.Arg736Thr) variant causes a missense 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. 17/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R736S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC3 NM_000122.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235
• Publications: 1 publications found

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

• trichothiodystrophy 2, photosensitive

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• xeroderma pigmentosum group B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08604574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC3	NM_000122.2	c.2207G>C	p.Arg736Thr	missense_variant	Exon 14 of 15	ENST00000285398.7	NP_000113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC3	ENST00000285398.7	c.2207G>C	p.Arg736Thr	missense_variant	Exon 14 of 15	1	NM_000122.2	ENSP00000285398.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251370 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		0.23
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.99	N;.
REVEL	Benign	0.076
Sift	Benign	0.27	T;.
Sift4G	Benign	0.39	T;.
Polyphen		0.0	B;.
Vest4		0.21
MutPred		0.33		Gain of glycosylation at R736 (P = 0.0138);.;
MVP		0.48
MPC		0.44
ClinPred		0.031	T
GERP RS		-3.2
Varity_R		0.058
gMVP		0.56
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs587778276; hg19: chr2-128016882;