19-45370684-G-C

Position:

• chr19-45370684-G-C

Variant summary

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

The ENST00000391941.6(ERCC2):​c.-519C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 834,764 control chromosomes in the GnomAD database, including 98,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (25874 hom., cov: 31)
  • Exomes 𝑓: 0.46 (73002 hom.)
• Consequence: ERCC2 ENST00000391941.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0260

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=-0.75).
• BP6: Variant 19-45370684-G-C is Benign according to our data. Variant chr19-45370684-G-C is described in ClinVar as [Benign]. Clinvar id is 1221224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391941.6	c.-519C>G		5_prime_UTR_variant	1/21	1		ENSP00000375805

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84183 AN: 151986 Hom.: 25824 Cov.: 31

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.457 AC: 311674 AN: 682660 Hom.: 73002 Cov.: 9 AF XY: 0.457 AC XY: 162929 AN XY: 356410

Gnomad4 AFR exome AF: 0.848

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.434

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.554 AC: 84289 AN: 152104 Hom.: 25874 Cov.: 31 AF XY: 0.550 AC XY: 40858 AN XY: 74334

Gnomad4 AFR AF: 0.845

Gnomad4 AMR AF: 0.468

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.471

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.519

Alfa AF: 0.303 Hom.: 651

Bravo AF: 0.574

Asia WGS AF: 0.497 AC: 1731 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	-0.75
CADD	Benign	3.8
DANN	Benign	0.39

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3810366; hg19: chr19-45873942; COSMIC: COSV55543445;