19-45353977-C-G

Position:

• chr19-45353977-C-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1666-643G>C		intron_variant		ENST00000391945.10	NP_000391.1
ERCC2	XM_011526611.3	c.1588-643G>C		intron_variant			XP_011524913.1
ERCC2	XR_001753633.3	n.1699-643G>C		intron_variant, non_coding_transcript_variant
ERCC2	XR_007066680.1	n.1621-643G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1666-643G>C		intron_variant		1	NM_000400.4	ENSP00000375809	P1

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

Gnomad4 AFR AF: 0.879

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.606

Gnomad4 OTH AF: 0.606

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs238415; hg19: chr19-45857235;