rs2134794

Variant names:

• chr2-127273303-A-C
• rs2134794
• NM_000122.2:c.1731-342T>G

Variant summary

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

The NM_000122.2(ERCC3):​c.1731-342T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 152,142 control chromosomes in the GnomAD database, including 3,281 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 0.20 (3281 hom., cov: 31)
• Consequence: ERCC3 NM_000122.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 16 publications found

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

• trichothiodystrophy 2, photosensitive

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• 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
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000122.2. 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
	ERCC3	NM_000122.2	MANE Select	c.1731-342T>G		intron	N/A	NP_000113.1	P19447
	ERCC3	NM_001303416.2		c.1539-342T>G		intron	N/A	NP_001290345.1
	ERCC3	NM_001303418.2		c.1539-342T>G		intron	N/A	NP_001290347.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC3	ENST00000285398.7	TSL:1 MANE Select	c.1731-342T>G		intron	N/A	ENSP00000285398.2	P19447
	ERCC3	ENST00000647169.1		c.1806-342T>G		intron	N/A	ENSP00000495619.1	A0A2R8Y6W8
	ERCC3	ENST00000918332.1		c.1782-342T>G		intron	N/A	ENSP00000588391.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30394 AN: 152024 Hom.: 3272 Cov.: 31

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.201

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.200 AC: 30421 AN: 152142 Hom.: 3281 Cov.: 31 AF XY: 0.203 AC XY: 15121 AN XY: 74386

African (AFR) AF: 0.133 AC: 5518 AN: 41528

American (AMR) AF: 0.173 AC: 2651 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 525 AN: 3462

East Asian (EAS) AF: 0.265 AC: 1366 AN: 5164

South Asian (SAS) AF: 0.337 AC: 1626 AN: 4820

European-Finnish (FIN) AF: 0.273 AC: 2890 AN: 10590

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.225 AC: 15279 AN: 67978

Other (OTH) AF: 0.208 AC: 441 AN: 2116

Alfa AF: 0.207 Hom.: 1205

Bravo AF: 0.187

Asia WGS AF: 0.314 AC: 1090 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.62
PhyloP100		0.20
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: rs2134794; hg19: chr2-128030879;