rs238414

Positions:

• chr19-45354562-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.1665+168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,070 control chromosomes in the GnomAD database, including 13,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.38 (13171 hom., cov: 33)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.155

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=-0.88).
• BP6: Variant 19-45354562-G-A is Benign according to our data. Variant chr19-45354562-G-A is described in ClinVar as [Benign]. Clinvar id is 1294046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1665+168C>T		intron_variant		ENST00000391945.10	NP_000391.1
ERCC2	XM_011526611.3	c.1587+168C>T		intron_variant			XP_011524913.1
ERCC2	XR_001753633.3	n.1698+168C>T		intron_variant
ERCC2	XR_007066680.1	n.1620+168C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1665+168C>T		intron_variant		1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57807 AN: 151952 Hom.: 13145 Cov.: 33

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.381 AC: 57893 AN: 152070 Hom.: 13171 Cov.: 33 AF XY: 0.375 AC XY: 27910 AN XY: 74342

Gnomad4 AFR AF: 0.642

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.314

Alfa AF: 0.328 Hom.: 1202

Bravo AF: 0.403

Asia WGS AF: 0.374 AC: 1298 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	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.95
DANN	Benign	0.57

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: rs238414; hg19: chr19-45857820; COSMIC: COSV67263222; COSMIC: COSV67263222;