2-216205503-A-G

Variant names:

• chr2-216205503-A-G
• rs41296835
• NM_021141.4:c.*301A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_021141.4(XRCC5):​c.*301A>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 0.00472 in 393,412 control chromosomes in the GnomAD database, including 33 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 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: XRCC5 NM_021141.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359
• Publications: 4 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=-0.64).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1571/152306) while in subpopulation AFR AF = 0.0362 (1503/41552). AF 95% confidence interval is 0.0347. There are 27 homozygotes in GnomAd4. There are 746 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1571 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021141.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC5	NM_021141.4	MANE Select	c.*301A>G		3_prime_UTR	Exon 21 of 21	NP_066964.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC5	ENST00000392132.7	TSL:1 MANE Select	c.*301A>G		3_prime_UTR	Exon 21 of 21	ENSP00000375977.2
	XRCC5	ENST00000392133.7	TSL:5	c.*301A>G		3_prime_UTR	Exon 23 of 23	ENSP00000375978.3
	XRCC5	ENST00000460284.5	TSL:1	n.*80A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1572 AN: 152188 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00118 AC: 284 AN: 241106 Hom.: 6 Cov.: 0 AF XY: 0.00111 AC XY: 141 AN XY: 127342

African (AFR) AF: 0.0309 AC: 218 AN: 7066

American (AMR) AF: 0.00183 AC: 16 AN: 8756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7700

East Asian (EAS) AF: 0.00 AC: 0 AN: 15552

South Asian (SAS) AF: 0.000205 AC: 5 AN: 24426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13996

Middle Eastern (MID) AF: 0.00438 AC: 5 AN: 1142

European-Non Finnish (NFE) AF: 0.0000608 AC: 9 AN: 148104

Other (OTH) AF: 0.00216 AC: 31 AN: 14364

GnomAD4 genome AF: 0.0103 AC: 1571 AN: 152306 Hom.: 27 Cov.: 32 AF XY: 0.0100 AC XY: 746 AN XY: 74486

African (AFR) AF: 0.0362 AC: 1503 AN: 41552

American (AMR) AF: 0.00327 AC: 50 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00427 Hom.: 3

Bravo AF: 0.0115

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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: rs41296835; hg19: chr2-217070226;