19-45351802-C-G

Position:

• chr19-45351802-C-G

Variant summary

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

The ENST00000391944.8(ERCC2):​c.*107G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,239,318 control chromosomes in the GnomAD database, including 75,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7368 hom., cov: 32)
  • Exomes 𝑓: 0.34 (67936 hom.)
• Consequence: ERCC2 ENST00000391944.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08

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=-0.89).
• BP6: Variant 19-45351802-C-G is Benign according to our data. Variant chr19-45351802-C-G is described in ClinVar as [Benign]. Clinvar id is 1182968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.2191-81G>C		intron_variant		ENST00000391945.10
ERCC2	XM_011526611.3	c.2113-81G>C		intron_variant
ERCC2	XR_001753633.3	n.2224-81G>C		intron_variant, non_coding_transcript_variant
ERCC2	XR_007066680.1	n.2146-81G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.2191-81G>C		intron_variant		1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43104 AN: 152098 Hom.: 7369 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.295

GnomAD4 exome AF: 0.345 AC: 374602 AN: 1087102 Hom.: 67936 AF XY: 0.348 AC XY: 192574 AN XY: 554082

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.0548

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.283 AC: 43102 AN: 152216 Hom.: 7368 Cov.: 32 AF XY: 0.285 AC XY: 21193 AN XY: 74416

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.0730

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.291

Alfa AF: 0.205 Hom.: 497

Bravo AF: 0.258

Asia WGS AF: 0.179 AC: 627 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	-0.89
CADD	Benign	0.45
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1799790; hg19: chr19-45855060;