rs238417

Variant names:

• chr19-45353210-G-C
• rs238417
• NM_000400.4:c.1758+32C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-45353210-G-C
• chr19-45353210-G-A
• chr19-45353210-G-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.1758+32C>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 1,610,776 control chromosomes in the GnomAD database, including 287,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33988 hom., cov: 30)
  • Exomes 𝑓: 0.59 (253278 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.93
• Publications: 19 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=-0.94).
• BP6: Variant 19-45353210-G-C is Benign according to our data. Variant chr19-45353210-G-C is described in ClinVar as Benign. ClinVar VariationId is 256016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 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.1758+32C>G		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1686+32C>G		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1680+32C>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.1758+32C>G		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1758+32C>G		intron	N/A	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1686+32C>G		intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99533 AN: 151742 Hom.: 33945 Cov.: 30

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.582

GnomAD2 exomes AF: 0.589 AC: 147518 AN: 250360 AF XY: 0.586

Gnomad AFR exome AF: 0.864

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.516

Gnomad FIN exome AF: 0.636

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.562

GnomAD4 exome AF: 0.587 AC: 856584 AN: 1458916 Hom.: 253278 Cov.: 34 AF XY: 0.586 AC XY: 425137 AN XY: 725918

African (AFR) AF: 0.871 AC: 29126 AN: 33426

American (AMR) AF: 0.522 AC: 23289 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 15733 AN: 26122

East Asian (EAS) AF: 0.495 AC: 19635 AN: 39676

South Asian (SAS) AF: 0.560 AC: 48248 AN: 86188

European-Finnish (FIN) AF: 0.637 AC: 34006 AN: 53362

Middle Eastern (MID) AF: 0.523 AC: 2999 AN: 5738

European-Non Finnish (NFE) AF: 0.584 AC: 647952 AN: 1109494

Other (OTH) AF: 0.590 AC: 35596 AN: 60290

GnomAD4 genome AF: 0.656 AC: 99632 AN: 151860 Hom.: 33988 Cov.: 30 AF XY: 0.652 AC XY: 48373 AN XY: 74232

African (AFR) AF: 0.858 AC: 35520 AN: 41400

American (AMR) AF: 0.542 AC: 8267 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2088 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2615 AN: 5124

South Asian (SAS) AF: 0.547 AC: 2620 AN: 4792

European-Finnish (FIN) AF: 0.646 AC: 6836 AN: 10574

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39614 AN: 67932

Other (OTH) AF: 0.582 AC: 1228 AN: 2110

Alfa AF: 0.553 Hom.: 3166

Bravo AF: 0.659

Asia WGS AF: 0.544 AC: 1893 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Xeroderma pigmentosum, group D (2)
-	-	1	Cerebrooculofacioskeletal syndrome 2 (1)
-	-	1	not specified (1)
-	-	1	Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.033
DANN	Benign	0.46
PhyloP100		-4.9
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: rs238417; hg19: chr19-45856468; COSMIC: COSV67270598; COSMIC: COSV67270598;