rs1799787

Variant names:

• chr19-45352886-G-A
• rs1799787
• NM_000400.4:c.1832-70C>T

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.1832-70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,446,924 control chromosomes in the GnomAD database, including 62,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5159 hom., cov: 28)
  • Exomes 𝑓: 0.29 (56933 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.136
• Publications: 44 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=-0.82).
• BP6: Variant 19-45352886-G-A is Benign according to our data. Variant chr19-45352886-G-A is described in ClinVar as Benign. ClinVar VariationId is 1244476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1832-70C>T		intron_variant	Intron 19 of 22	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1832-70C>T		intron_variant	Intron 19 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36188 AN: 151072 Hom.: 5160 Cov.: 28

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.0718

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.288 AC: 372694 AN: 1295734 Hom.: 56933 Cov.: 19 AF XY: 0.291 AC XY: 189509 AN XY: 652300

African (AFR) AF: 0.0980 AC: 2969 AN: 30286

American (AMR) AF: 0.173 AC: 7433 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 8762 AN: 25004

East Asian (EAS) AF: 0.0544 AC: 2098 AN: 38588

South Asian (SAS) AF: 0.318 AC: 26327 AN: 82680

European-Finnish (FIN) AF: 0.365 AC: 18108 AN: 49544

Middle Eastern (MID) AF: 0.332 AC: 1649 AN: 4966

European-Non Finnish (NFE) AF: 0.300 AC: 290303 AN: 966844

Other (OTH) AF: 0.274 AC: 15045 AN: 54904

GnomAD4 genome AF: 0.239 AC: 36184 AN: 151190 Hom.: 5159 Cov.: 28 AF XY: 0.242 AC XY: 17849 AN XY: 73834

African (AFR) AF: 0.106 AC: 4384 AN: 41258

American (AMR) AF: 0.206 AC: 3130 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3464

East Asian (EAS) AF: 0.0714 AC: 365 AN: 5112

South Asian (SAS) AF: 0.310 AC: 1470 AN: 4748

European-Finnish (FIN) AF: 0.372 AC: 3902 AN: 10484

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.308 AC: 20834 AN: 67628

Other (OTH) AF: 0.240 AC: 501 AN: 2086

Alfa AF: 0.294 Hom.: 13710

Bravo AF: 0.217

Asia WGS AF: 0.157 AC: 550 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.73
DANN	Benign	0.78
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799787; hg19: chr19-45856144;