rs1799787

Positions:

• chr19-45352886-G-A

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.1832-70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,446,924 control chromosomes in the GnomAD database, including 62,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5159 hom., cov: 28)
  • Exomes 𝑓: 0.29 (56933 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.136

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-45352886-G-A is Benign according to our data. Variant chr19-45352886-G-A is described in ClinVar as [Benign]. Clinvar id is 1244476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1832-70C>T		intron_variant		ENST00000391945.10	NP_000391.1
ERCC2	XM_011526611.3	c.1754-70C>T		intron_variant			XP_011524913.1
ERCC2	XR_001753633.3	n.1865-70C>T		intron_variant
ERCC2	XR_007066680.1	n.1787-70C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1832-70C>T		intron_variant		1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36188 AN: 151072 Hom.: 5160 Cov.: 28

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.0718

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.288 AC: 372694 AN: 1295734 Hom.: 56933 Cov.: 19 AF XY: 0.291 AC XY: 189509 AN XY: 652300

Gnomad4 AFR exome AF: 0.0980

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.0544

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.239 AC: 36184 AN: 151190 Hom.: 5159 Cov.: 28 AF XY: 0.242 AC XY: 17849 AN XY: 73834

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.0714

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.240

Alfa AF: 0.302 Hom.: 10534

Bravo AF: 0.217

Asia WGS AF: 0.157 AC: 550 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	-0.82
CADD	Benign	0.73
DANN	Benign	0.78

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: rs1799787; hg19: chr19-45856144;