19-45351072-A-C

Position:

• chr19-45351072-A-C

Variant summary

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

The NM_000400.4(ERCC2):​c.*557T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,613,514 control chromosomes in the GnomAD database, including 3,180 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 0.049 (190 hom., cov: 31)
  • Exomes 𝑓: 0.061 (2990 hom.)
• Consequence: ERCC2 NM_000400.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940

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]

KLC3 (HGNC:20717): (kinesin light chain 3) This gene encodes a member of the kinesin light chain gene family. Kinesins are molecular motors involved in the transport of cargo along microtubules, and are composed of two kinesin heavy chain (KHC) and two kinesin light chain (KLC) molecules. KLCs are thought to typically be involved in binding cargo and regulating kinesin activity. In the rat, a protein similar to this gene product is expressed in post-meiotic spermatids, where it associates with structural components of sperm tails and mitochondria. [provided by RefSeq, Jul 2008]

ERCC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.*557T>G		3_prime_UTR_variant	23/23	ENST00000391945.10	NP_000391.1
KLC3	NM_177417.3	c.1443+55A>C		intron_variant		ENST00000391946.7	NP_803136.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945	c.*557T>G		3_prime_UTR_variant	23/23	1	NM_000400.4	ENSP00000375809.4
KLC3	ENST00000391946.7	c.1443+55A>C		intron_variant		1	NM_177417.3	ENSP00000375810.2

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7379 AN: 152088 Hom.: 189 Cov.: 31

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0502

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0635

Gnomad OTH AF: 0.0561

GnomAD4 exome AF: 0.0610 AC: 89205 AN: 1461308 Hom.: 2990 Cov.: 34 AF XY: 0.0609 AC XY: 44263 AN XY: 726896

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.0272

Gnomad4 ASJ exome AF: 0.0576

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.0510

Gnomad4 NFE exome AF: 0.0667

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.0485 AC: 7387 AN: 152206 Hom.: 190 Cov.: 31 AF XY: 0.0472 AC XY: 3515 AN XY: 74432

Gnomad4 AFR AF: 0.0360

Gnomad4 AMR AF: 0.0340

Gnomad4 ASJ AF: 0.0502

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0484

Gnomad4 FIN AF: 0.0454

Gnomad4 NFE AF: 0.0636

Gnomad4 OTH AF: 0.0556

Alfa AF: 0.0256 Hom.: 15

Bravo AF: 0.0476

Asia WGS AF: 0.0200 AC: 72 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.26
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3916898; hg19: chr19-45854330;