rs238403

Variant names:

• chr19-45361959-T-C
• rs238403
• NM_000400.4:c.1119-317A>G

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.1119-317A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 350,540 control chromosomes in the GnomAD database, including 64,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32989 hom., cov: 30)
  • Exomes 𝑓: 0.56 (31637 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47
• Publications: 10 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, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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=-1.03).
• BP6: Variant 19-45361959-T-C is Benign according to our data. Variant chr19-45361959-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.1119-317A>G		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1047-317A>G		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1041-317A>G		intron	N/A	NP_001427285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.1119-317A>G		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1119-317A>G		intron	N/A	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1047-317A>G		intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97092 AN: 151754 Hom.: 32934 Cov.: 30

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.598

GnomAD4 exome AF: 0.559 AC: 111104 AN: 198670 Hom.: 31637 Cov.: 0 AF XY: 0.563 AC XY: 60541 AN XY: 107518

African (AFR) AF: 0.887 AC: 5002 AN: 5640

American (AMR) AF: 0.505 AC: 5066 AN: 10022

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 3058 AN: 5150

East Asian (EAS) AF: 0.495 AC: 4872 AN: 9842

South Asian (SAS) AF: 0.594 AC: 21950 AN: 36940

European-Finnish (FIN) AF: 0.558 AC: 4559 AN: 8166

Middle Eastern (MID) AF: 0.588 AC: 808 AN: 1374

European-Non Finnish (NFE) AF: 0.540 AC: 60212 AN: 111466

Other (OTH) AF: 0.554 AC: 5577 AN: 10070

GnomAD4 genome AF: 0.640 AC: 97198 AN: 151870 Hom.: 32989 Cov.: 30 AF XY: 0.636 AC XY: 47174 AN XY: 74206

African (AFR) AF: 0.886 AC: 36714 AN: 41432

American (AMR) AF: 0.529 AC: 8079 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2040 AN: 3470

East Asian (EAS) AF: 0.498 AC: 2566 AN: 5156

South Asian (SAS) AF: 0.587 AC: 2830 AN: 4818

European-Finnish (FIN) AF: 0.568 AC: 5964 AN: 10506

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37048 AN: 67918

Other (OTH) AF: 0.597 AC: 1257 AN: 2104

Alfa AF: 0.606 Hom.: 3611

Bravo AF: 0.649

Asia WGS AF: 0.564 AC: 1963 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.30
PhyloP100		-1.5
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: rs238403; hg19: chr19-45865217; COSMIC: COSV55545626; COSMIC: COSV55545626;