rs238403

Positions:

• chr19-45361959-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000400.4(ERCC2):​c.1119-317A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 350,540 control chromosomes in the GnomAD database, including 64,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32989 hom., cov: 30)
  • Exomes 𝑓: 0.56 (31637 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 19-45361959-T-C is Benign according to our data. Variant chr19-45361959-T-C is described in ClinVar as [Benign]. Clinvar id is 1267350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1119-317A>G		intron_variant		ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1119-317A>G		intron_variant		1	NM_000400.4	ENSP00000375809	P1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97092 AN: 151754 Hom.: 32934 Cov.: 30

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.598

GnomAD4 exome AF: 0.559 AC: 111104 AN: 198670 Hom.: 31637 Cov.: 0 AF XY: 0.563 AC XY: 60541 AN XY: 107518

Gnomad4 AFR exome AF: 0.887

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.594

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.558

Gnomad4 NFE exome AF: 0.540

Gnomad4 OTH exome AF: 0.554

GnomAD4 genome AF: 0.640 AC: 97198 AN: 151870 Hom.: 32989 Cov.: 30 AF XY: 0.636 AC XY: 47174 AN XY: 74206

Gnomad4 AFR AF: 0.886

Gnomad4 AMR AF: 0.529

Gnomad4 ASJ AF: 0.588

Gnomad4 EAS AF: 0.498

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.597

Alfa AF: 0.606 Hom.: 3611

Bravo AF: 0.649

Asia WGS AF: 0.564 AC: 1963 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.30

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

LitVar

Other links and lift over

dbSNP: rs238403; hg19: chr19-45865217; COSMIC: COSV55545626; COSMIC: COSV55545626;