rs1799788

chr19-45352842-G-Achr19-45352842-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000400.4(ERCC2):c.1832-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,609,886 control chromosomes in the GnomAD database, including 2,855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (159 hom., cov: 31)
  • Exomes 𝑓: 0.058 (2696 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.211

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=-0.87).
• BP6: Variant 19-45352842-G-A is Benign according to our data. Variant chr19-45352842-G-A is described in ClinVar as [Benign]. Clinvar id is 1248418.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-45352842-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.1832-26C>T		intron_variant		ENST00000391945.10
ERCC2	XM_011526611.3	c.1754-26C>T		intron_variant
ERCC2	XR_001753633.3	n.1865-26C>T		intron_variant, non_coding_transcript_variant
ERCC2	XR_007066680.1	n.1787-26C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.1832-26C>T		intron_variant		1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6728 AN: 151894 Hom.: 157 Cov.: 31

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0601

Gnomad OTH AF: 0.0480

GnomAD3 exomes AF: 0.0467 AC: 11616 AN: 248820 Hom.: 341 AF XY: 0.0481 AC XY: 6483 AN XY: 134700

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0548

GnomAD4 exome AF: 0.0579 AC: 84444 AN: 1457874 Hom.: 2696 Cov.: 35 AF XY: 0.0578 AC XY: 41918 AN XY: 725458

Gnomad4 AFR exome AF: 0.0288

Gnomad4 AMR exome AF: 0.0238

Gnomad4 ASJ exome AF: 0.0509

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0498

Gnomad4 FIN exome AF: 0.0501

Gnomad4 NFE exome AF: 0.0636

Gnomad4 OTH exome AF: 0.0560

GnomAD4 genome AF: 0.0443 AC: 6738 AN: 152012 Hom.: 159 Cov.: 31 AF XY: 0.0431 AC XY: 3206 AN XY: 74320

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0465

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.0601

Gnomad4 OTH AF: 0.0475

Alfa AF: 0.0521 Hom.: 44

Bravo AF: 0.0430

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.64
Dann	Benign	0.76

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: rs1799788; hg19: chr19-45856100; COSMIC: COSV67266443; COSMIC: COSV67266443;