2-216190448-A-G

Variant names:

• chr2-216190448-A-G
• rs12470053
• NM_021141.4:c.1944+114A>G

Variant summary

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

The NM_021141.4(XRCC5):​c.1944+114A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 854,146 control chromosomes in the GnomAD database, including 194,950 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 0.72 (41448 hom., cov: 32)
  • Exomes 𝑓: 0.65 (153502 hom.)
• Consequence: XRCC5 NM_021141.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365
• Publications: 5 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC5	NM_021141.4	c.1944+114A>G		intron_variant	Intron 17 of 20	ENST00000392132.7	NP_066964.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC5	ENST00000392132.7	c.1944+114A>G		intron_variant	Intron 17 of 20	1	NM_021141.4	ENSP00000375977.2
XRCC5	ENST00000460284.5	n.2486+114A>G		intron_variant	Intron 14 of 17	1
XRCC5	ENST00000392133.7	c.1944+114A>G		intron_variant	Intron 19 of 22	5		ENSP00000375978.3

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110111 AN: 152042 Hom.: 41382 Cov.: 32

Gnomad AFR AF: 0.905

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.715

GnomAD4 exome AF: 0.651 AC: 457144 AN: 701986 Hom.: 153502 AF XY: 0.654 AC XY: 237433 AN XY: 362806

African (AFR) AF: 0.915 AC: 15806 AN: 17278

American (AMR) AF: 0.797 AC: 19443 AN: 24404

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 11052 AN: 16566

East Asian (EAS) AF: 0.938 AC: 30664 AN: 32700

South Asian (SAS) AF: 0.771 AC: 41689 AN: 54040

European-Finnish (FIN) AF: 0.675 AC: 24588 AN: 36444

Middle Eastern (MID) AF: 0.701 AC: 2898 AN: 4134

European-Non Finnish (NFE) AF: 0.597 AC: 287537 AN: 481712

Other (OTH) AF: 0.676 AC: 23467 AN: 34708

GnomAD4 genome AF: 0.724 AC: 110235 AN: 152160 Hom.: 41448 Cov.: 32 AF XY: 0.731 AC XY: 54372 AN XY: 74374

African (AFR) AF: 0.906 AC: 37623 AN: 41546

American (AMR) AF: 0.763 AC: 11671 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2335 AN: 3468

East Asian (EAS) AF: 0.947 AC: 4908 AN: 5184

South Asian (SAS) AF: 0.784 AC: 3785 AN: 4826

European-Finnish (FIN) AF: 0.661 AC: 6985 AN: 10562

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40711 AN: 67960

Other (OTH) AF: 0.716 AC: 1515 AN: 2116

Alfa AF: 0.666 Hom.: 4995

Bravo AF: 0.741

Asia WGS AF: 0.847 AC: 2946 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.33
PhyloP100		-0.36
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: rs12470053; hg19: chr2-217055171;