NM_000400.4:c.1666-643G>C

Variant names:

• chr19-45353977-C-G
• rs238415
• NM_000400.4:c.1666-643G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000400.4(ERCC2):​c.1666-643G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 152,090 control chromosomes in the GnomAD database, including 36,171 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (36171 hom., cov: 33)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0860
• Publications: 18 publications found

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1666-643G>C		intron_variant	Intron 17 of 22	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1666-643G>C		intron_variant	Intron 17 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102826 AN: 151972 Hom.: 36112 Cov.: 33

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.606

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.677 AC: 102942 AN: 152090 Hom.: 36171 Cov.: 33 AF XY: 0.672 AC XY: 49957 AN XY: 74324

African (AFR) AF: 0.879 AC: 36510 AN: 41526

American (AMR) AF: 0.558 AC: 8528 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2148 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2637 AN: 5166

South Asian (SAS) AF: 0.563 AC: 2710 AN: 4812

European-Finnish (FIN) AF: 0.670 AC: 7084 AN: 10568

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41182 AN: 67948

Other (OTH) AF: 0.606 AC: 1278 AN: 2110

Alfa AF: 0.512 Hom.: 1357

Bravo AF: 0.679

Asia WGS AF: 0.554 AC: 1930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.0
DANN	Benign	0.46
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs238415; hg19: chr19-45857235;