2-216109091-C-T

Variant names:

• chr2-216109091-C-T
• rs11685387
• ENST00000392133.7:c.-346C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC5	ENST00000392133.7	c.-346C>T		splice_region_variant	Exon 3 of 23	5		ENSP00000375978.3
XRCC5	ENST00000392133.7	c.-346C>T		5_prime_UTR_variant	Exon 3 of 23	5		ENSP00000375978.3
XRCC5	ENST00000429133.5	n.-240C>T		upstream_gene_variant		4

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

African (AFR) AF: 0.257 AC: 5909 AN: 22992

American (AMR) AF: 0.516 AC: 6900 AN: 13384

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 3985 AN: 12440

East Asian (EAS) AF: 0.685 AC: 12792 AN: 18676

South Asian (SAS) AF: 0.209 AC: 12506 AN: 59796

European-Finnish (FIN) AF: 0.343 AC: 4479 AN: 13048

Middle Eastern (MID) AF: 0.263 AC: 688 AN: 2612

European-Non Finnish (NFE) AF: 0.266 AC: 242062 AN: 909876

Other (OTH) AF: 0.286 AC: 11804 AN: 41338

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

African (AFR) AF: 0.263 AC: 10909 AN: 41494

American (AMR) AF: 0.460 AC: 7037 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1105 AN: 3472

East Asian (EAS) AF: 0.672 AC: 3480 AN: 5178

South Asian (SAS) AF: 0.221 AC: 1067 AN: 4828

European-Finnish (FIN) AF: 0.361 AC: 3814 AN: 10556

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.271 AC: 18419 AN: 68020

Other (OTH) AF: 0.326 AC: 688 AN: 2112

Alfa AF: 0.291 Hom.: 4256

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
PhyloP100		-1.3
PromoterAI		-0.085	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11685387; hg19: chr2-216973814;