19-45363958-TG-TGG

Variant names:

• chr19-45363958-T-TG
• rs766117419
• NM_000400.4:c.949+27dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000400.4(ERCC2):​c.949+27dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,531,696 control chromosomes in the GnomAD database, including 55,811 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (14555 hom., cov: 0)
  • Exomes 𝑓: 0.22 (41256 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0850
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 19-45363958-T-TG is Benign according to our data. Variant chr19-45363958-T-TG is described in ClinVar as Benign. ClinVar VariationId is 256023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000400.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.949+27dupC		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.877+27dupC		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.871+27dupC		intron	N/A	NP_001427285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.949+27_949+28insC		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.949+27_949+28insC		intron	N/A	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.877+27_877+28insC		intron	N/A	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55284 AN: 151798 Hom.: 14516 Cov.: 0

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.275 AC: 37160 AN: 135026 AF XY: 0.264

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.223 AC: 307955 AN: 1379780 Hom.: 41256 Cov.: 36 AF XY: 0.222 AC XY: 151308 AN XY: 681302

African (AFR) AF: 0.771 AC: 24294 AN: 31518

American (AMR) AF: 0.310 AC: 11070 AN: 35742

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 5863 AN: 25092

East Asian (EAS) AF: 0.444 AC: 15865 AN: 35716

South Asian (SAS) AF: 0.249 AC: 19781 AN: 79298

European-Finnish (FIN) AF: 0.199 AC: 7027 AN: 35342

Middle Eastern (MID) AF: 0.199 AC: 1083 AN: 5438

European-Non Finnish (NFE) AF: 0.194 AC: 208109 AN: 1073976

Other (OTH) AF: 0.258 AC: 14863 AN: 57658

GnomAD4 genome AF: 0.365 AC: 55382 AN: 151916 Hom.: 14555 Cov.: 0 AF XY: 0.361 AC XY: 26786 AN XY: 74256

African (AFR) AF: 0.744 AC: 30875 AN: 41474

American (AMR) AF: 0.294 AC: 4493 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 800 AN: 3464

East Asian (EAS) AF: 0.449 AC: 2314 AN: 5158

South Asian (SAS) AF: 0.244 AC: 1176 AN: 4826

European-Finnish (FIN) AF: 0.196 AC: 2071 AN: 10550

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12868 AN: 67852

Other (OTH) AF: 0.314 AC: 661 AN: 2104

Alfa AF: 0.160 Hom.: 408

Bravo AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.085
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: rs766117419; hg19: chr19-45867216; COSMIC: COSV99059896; COSMIC: COSV99059896;