rs3916840

Variant names:

• chr19-45359039-G-A
• rs3916840
• NM_000400.4:c.1238-1340C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000400.4(ERCC2):​c.1238-1340C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 620,444 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0030 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (69 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1238-1340C>T		intron_variant	Intron 12 of 22	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1238-1340C>T		intron_variant	Intron 12 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152198 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0660

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00556 AC: 2605 AN: 468128 Hom.: 69 AF XY: 0.00568 AC XY: 1413 AN XY: 248600

African (AFR) AF: 0.00123 AC: 16 AN: 12990

American (AMR) AF: 0.0000455 AC: 1 AN: 21988

Ashkenazi Jewish (ASJ) AF: 0.000825 AC: 12 AN: 14540

East Asian (EAS) AF: 0.0597 AC: 1871 AN: 31342

South Asian (SAS) AF: 0.0101 AC: 474 AN: 46922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32178

Middle Eastern (MID) AF: 0.00357 AC: 13 AN: 3642

European-Non Finnish (NFE) AF: 0.0000828 AC: 23 AN: 277754

Other (OTH) AF: 0.00728 AC: 195 AN: 26772

GnomAD4 genome AF: 0.00301 AC: 459 AN: 152316 Hom.: 21 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74490

African (AFR) AF: 0.000577 AC: 24 AN: 41570

American (AMR) AF: 0.00111 AC: 17 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.0655 AC: 339 AN: 5172

South Asian (SAS) AF: 0.0132 AC: 64 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.37
PhyloP100		0.055
Mutation Taster		=100/0	polymorphism

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: rs3916840; hg19: chr19-45862297; COSMIC: COSV107284533; COSMIC: COSV107284533;