19-45353668-C-G

Variant names:

• chr19-45353668-C-G
• rs3916874
• NM_000400.4:c.1666-334G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000400.4(ERCC2):​c.1666-334G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,126 control chromosomes in the GnomAD database, including 3,416 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 0.19 (3416 hom., cov: 32)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1666-334G>C		intron_variant	Intron 17 of 22	ENST00000391945.10	NP_000391.1
ERCC2	XM_011526611.3	c.1588-334G>C		intron_variant	Intron 16 of 21		XP_011524913.1
ERCC2	XR_001753633.3	n.1699-334G>C		intron_variant	Intron 17 of 23
ERCC2	XR_007066680.1	n.1621-334G>C		intron_variant	Intron 16 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1666-334G>C		intron_variant	Intron 17 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28421 AN: 152008 Hom.: 3410 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.187 AC: 28444 AN: 152126 Hom.: 3416 Cov.: 32 AF XY: 0.183 AC XY: 13576 AN XY: 74364

Gnomad4 AFR AF: 0.0490

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.172

Alfa AF: 0.226 Hom.: 572

Bravo AF: 0.178

Asia WGS AF: 0.184 AC: 640 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.7
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs3916874; hg19: chr19-45856926;