rs1799783

Variant names:

• chr19-45368778-C-T
• rs1799783
• NM_000400.4:c.247-35G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000400.4(ERCC2):​c.247-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,571,972 control chromosomes in the GnomAD database, including 253,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32443 hom., cov: 32)
  • Exomes 𝑓: 0.56 (221266 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.77
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-45368778-C-T is Benign according to our data. Variant chr19-45368778-C-T is described in ClinVar as Benign. ClinVar VariationId is 256020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.247-35G>A		intron_variant	Intron 4 of 22	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.247-35G>A		intron_variant	Intron 4 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96627 AN: 151884 Hom.: 32391 Cov.: 32

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.575 AC: 129793 AN: 225820 AF XY: 0.572

Gnomad AFR exome AF: 0.875

Gnomad AMR exome AF: 0.516

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.591

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.555 AC: 788211 AN: 1419970 Hom.: 221266 Cov.: 25 AF XY: 0.556 AC XY: 393502 AN XY: 707222

African (AFR) AF: 0.882 AC: 28719 AN: 32550

American (AMR) AF: 0.512 AC: 21315 AN: 41642

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 15217 AN: 25718

East Asian (EAS) AF: 0.494 AC: 19222 AN: 38942

South Asian (SAS) AF: 0.600 AC: 50722 AN: 84468

European-Finnish (FIN) AF: 0.589 AC: 30940 AN: 52558

Middle Eastern (MID) AF: 0.593 AC: 3314 AN: 5584

European-Non Finnish (NFE) AF: 0.542 AC: 585365 AN: 1079570

Other (OTH) AF: 0.567 AC: 33397 AN: 58938

GnomAD4 genome AF: 0.636 AC: 96731 AN: 152002 Hom.: 32443 Cov.: 32 AF XY: 0.633 AC XY: 47048 AN XY: 74272

African (AFR) AF: 0.869 AC: 36033 AN: 41478

American (AMR) AF: 0.525 AC: 8008 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2028 AN: 3472

East Asian (EAS) AF: 0.501 AC: 2581 AN: 5156

South Asian (SAS) AF: 0.586 AC: 2817 AN: 4806

European-Finnish (FIN) AF: 0.589 AC: 6226 AN: 10562

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37103 AN: 67960

Other (OTH) AF: 0.593 AC: 1250 AN: 2108

Alfa AF: 0.603 Hom.: 5388

Bravo AF: 0.643

Asia WGS AF: 0.563 AC: 1961 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group D Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebrooculofacioskeletal syndrome 2 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Trichothiodystrophy 1, photosensitive Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.82
DANN	Benign	0.47
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1799783; hg19: chr19-45872036;