2-216109091-C-T

Position:

• chr2-216109091-C-T

Variant summary

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

The ENST00000392133.7(XRCC5):​c.-346C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,246,312 control chromosomes in the GnomAD database, including 52,024 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (7903 hom., cov: 34)
  • Exomes 𝑓: 0.28 (44121 hom.)
• Consequence: XRCC5 ENST00000392133.7 splice_region
• Scores: Splicing: ADA: 0.000008232
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35

Genes affected

XRCC5 (HGNC:12833): (X-ray repair cross complementing 5) The protein encoded by this gene is the 80-kilodalton subunit of the Ku heterodimer protein which is also known as ATP-dependant DNA helicase II or DNA repair protein XRCC5. Ku is the DNA-binding component of the DNA-dependent protein kinase, and it functions together with the DNA ligase IV-XRCC4 complex in the repair of DNA double-strand break by non-homologous end joining and the completion of V(D)J recombination events. This gene functionally complements Chinese hamster xrs-6, a mutant defective in DNA double-strand break repair and in ability to undergo V(D)J recombination. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.216109091C>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC5	ENST00000392133.7	c.-346C>T		splice_region_variant	3/23	5		ENSP00000375978.3
XRCC5	ENST00000392133	c.-346C>T		5_prime_UTR_variant	3/23	5		ENSP00000375978.3

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46883 AN: 152032 Hom.: 7890 Cov.: 34

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.275 AC: 301125 AN: 1094162 Hom.: 44121 Cov.: 29 AF XY: 0.274 AC XY: 143446 AN XY: 524404

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.685

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.308 AC: 46908 AN: 152150 Hom.: 7903 Cov.: 34 AF XY: 0.315 AC XY: 23429 AN XY: 74380

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.460

Gnomad4 ASJ AF: 0.318

Gnomad4 EAS AF: 0.672

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.326

Alfa AF: 0.271 Hom.: 2215

Bravo AF: 0.323

Asia WGS AF: 0.384 AC: 1337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.76
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000082
dbscSNV1_RF	Benign	0.0
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: rs11685387; hg19: chr2-216973814;