rs73559309

Positions:

• chr19-45361758-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.1119-116C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 795,316 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (47 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -1.53

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=-0.93).
• BP6: Variant 19-45361758-G-C is Benign according to our data. Variant chr19-45361758-G-C is described in ClinVar as [Benign]. Clinvar id is 135530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1119-116C>G		intron_variant		ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1119-116C>G		intron_variant		1	NM_000400.4	ENSP00000375809	P1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2875 AN: 152140 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00512 AC: 934 AN: 182260 Hom.: 26 AF XY: 0.00373 AC XY: 366 AN XY: 98054

Gnomad AFR exome AF: 0.0723

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.000225

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.00257 AC: 1652 AN: 643058 Hom.: 47 Cov.: 8 AF XY: 0.00210 AC XY: 724 AN XY: 344654

Gnomad4 AFR exome AF: 0.0673

Gnomad4 AMR exome AF: 0.00422

Gnomad4 ASJ exome AF: 0.000198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00645

GnomAD4 genome AF: 0.0189 AC: 2885 AN: 152258 Hom.: 93 Cov.: 33 AF XY: 0.0178 AC XY: 1328 AN XY: 74454

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0114 Hom.: 10

Bravo AF: 0.0226

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0060
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs73559309; hg19: chr19-45865016;