rs111562095

chr19-45361788-A-Cchr19-45361788-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000400.4(ERCC2):c.1119-146T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 703,866 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (47 hom., cov: 33)
  • Exomes 𝑓: 0.023 (204 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.0230

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-45361788-A-C is Benign according to our data. Variant chr19-45361788-A-C is described in ClinVar as [Benign]. Clinvar id is 135531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0195 (2964/152146) while in subpopulation NFE AF= 0.0261 (1777/67990). AF 95% confidence interval is 0.0251. There are 47 homozygotes in gnomad4. There are 1442 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.1119-146T>G		intron_variant		ENST00000391945.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.1119-146T>G		intron_variant		1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2963 AN: 152028 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0211 AC: 3165 AN: 149676 Hom.: 58 AF XY: 0.0204 AC XY: 1627 AN XY: 79732

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.0000863

Gnomad SAS exome AF: 0.00479

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0234 AC: 12914 AN: 551720 Hom.: 204 Cov.: 5 AF XY: 0.0223 AC XY: 6661 AN XY: 298342

Gnomad4 AFR exome AF: 0.00368

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0597

Gnomad4 EAS exome AF: 0.0000317

Gnomad4 SAS exome AF: 0.00517

Gnomad4 FIN exome AF: 0.0446

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0195 AC: 2964 AN: 152146 Hom.: 47 Cov.: 33 AF XY: 0.0194 AC XY: 1442 AN XY: 74380

Gnomad4 AFR AF: 0.00499

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0514

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0260 Hom.: 9

Bravo AF: 0.0166

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2019

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.3
Dann	Benign	0.64

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: rs111562095; hg19: chr19-45865046; COSMIC: COSV55539928; COSMIC: COSV55539928;