19-45353791-T-C

Variant names:

• chr19-45353791-T-C
• rs238416
• NM_000400.4:c.1666-457A>G

Variant summary

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

The NM_000400.4(ERCC2):​c.1666-457A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 152,094 control chromosomes in the GnomAD database, including 39,139 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 0.71 (39139 hom., cov: 32)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.982
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.895 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.1666-457A>G		intron	N/A	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1594-457A>G		intron	N/A	NP_001427284.1
	ERCC2	NM_001440356.1		c.1588-457A>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.1666-457A>G		intron	N/A	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1666-457A>G		intron	N/A	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1594-457A>G		intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107208 AN: 151976 Hom.: 39074 Cov.: 32

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.638

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

GnomAD4 genome AF: 0.706 AC: 107329 AN: 152094 Hom.: 39139 Cov.: 32 AF XY: 0.700 AC XY: 52034 AN XY: 74324

African (AFR) AF: 0.902 AC: 37460 AN: 41512

American (AMR) AF: 0.574 AC: 8770 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2254 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2623 AN: 5148

South Asian (SAS) AF: 0.595 AC: 2866 AN: 4816

European-Finnish (FIN) AF: 0.691 AC: 7318 AN: 10588

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43815 AN: 67974

Other (OTH) AF: 0.638 AC: 1341 AN: 2102

Alfa AF: 0.668 Hom.: 88109

Bravo AF: 0.707

Asia WGS AF: 0.566 AC: 1973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.98
DANN	Benign	0.87
PhyloP100		-0.98
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: rs238416; hg19: chr19-45857049;