rs41257924

Variant names:

• chr2-216141316-T-C
• rs41257924
• NM_021141.4:c.1473T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_021141.4(XRCC5):​c.1473T>C​(p.Phe491Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,614,050 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (40 hom.)
• Consequence: XRCC5 NM_021141.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.767
• Publications: 7 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-216141316-T-C is Benign according to our data. Variant chr2-216141316-T-C is described in ClinVar as Benign. ClinVar VariationId is 775186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.767 with no splicing effect.
• BS2: High AC in GnomAd4 at 695 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC5	NM_021141.4	MANE Select	c.1473T>C	p.Phe491Phe	synonymous	Exon 13 of 21	NP_066964.1	P13010

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC5	ENST00000392132.7	TSL:1 MANE Select	c.1473T>C	p.Phe491Phe	synonymous	Exon 13 of 21	ENSP00000375977.2	P13010
	XRCC5	ENST00000460284.5	TSL:1	n.2015T>C		non_coding_transcript_exon	Exon 10 of 18
	XRCC5	ENST00000947464.1		c.1473T>C	p.Phe491Phe	synonymous	Exon 13 of 22	ENSP00000617523.1

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 696 AN: 152130 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00604

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00551 AC: 1384 AN: 251326 AF XY: 0.00596

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00656

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00618 AC: 9035 AN: 1461802 Hom.: 40 Cov.: 31 AF XY: 0.00642 AC XY: 4669 AN XY: 727212

African (AFR) AF: 0.000926 AC: 31 AN: 33476

American (AMR) AF: 0.00331 AC: 148 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 361 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00763 AC: 658 AN: 86254

European-Finnish (FIN) AF: 0.00672 AC: 359 AN: 53404

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.00638 AC: 7099 AN: 1111964

Other (OTH) AF: 0.00563 AC: 340 AN: 60394

GnomAD4 genome AF: 0.00456 AC: 695 AN: 152248 Hom.: 5 Cov.: 32 AF XY: 0.00474 AC XY: 353 AN XY: 74444

African (AFR) AF: 0.00103 AC: 43 AN: 41550

American (AMR) AF: 0.00706 AC: 108 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4826

European-Finnish (FIN) AF: 0.00604 AC: 64 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00572 AC: 389 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00576 Hom.: 4

Bravo AF: 0.00412

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.8
DANN	Benign	0.52
PhyloP100		0.77
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: rs41257924; hg19: chr2-217006039; COSMIC: COSV101079998;