19-45354562-G-A

Variant names:

• chr19-45354562-G-A
• rs238414
• NM_000400.4:c.1665+168C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000391945.10(ERCC2):​c.1665+168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,070 control chromosomes in the GnomAD database, including 13,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.38 (13171 hom., cov: 33)
• Consequence: ERCC2 ENST00000391945.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.155
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-45354562-G-A is Benign according to our data. Variant chr19-45354562-G-A is described in ClinVar as Benign. ClinVar VariationId is 1294046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000391945.10. 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.1665+168C>T		intron	N/A	NP_000391.1
	ERCC2	NM_001440355.1		c.1593+168C>T		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1587+168C>T		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.1665+168C>T		intron	N/A	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.1665+168C>T		intron	N/A	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.1593+168C>T		intron	N/A	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57807 AN: 151952 Hom.: 13145 Cov.: 33

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.381 AC: 57893 AN: 152070 Hom.: 13171 Cov.: 33 AF XY: 0.375 AC XY: 27910 AN XY: 74342

African (AFR) AF: 0.642 AC: 26620 AN: 41478

American (AMR) AF: 0.319 AC: 4879 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 875 AN: 3468

East Asian (EAS) AF: 0.420 AC: 2164 AN: 5148

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4826

European-Finnish (FIN) AF: 0.272 AC: 2881 AN: 10588

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18299 AN: 67962

Other (OTH) AF: 0.314 AC: 663 AN: 2112

Alfa AF: 0.328 Hom.: 1202

Bravo AF: 0.403

Asia WGS AF: 0.374 AC: 1298 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.88
CADD	Benign	0.95
DANN	Benign	0.57
PhyloP100		-0.15
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: rs238414; hg19: chr19-45857820; COSMIC: COSV67263222; COSMIC: COSV67263222;