2-216137193-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_021141.4(XRCC5):c.1219G>A(p.Val407Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: XRCC5 NM_021141.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, XRCC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.23571345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC5	NM_021141.4	c.1219G>A	p.Val407Met	missense_variant	11/21	ENST00000392132.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC5	ENST00000392132.7	c.1219G>A	p.Val407Met	missense_variant	11/21	1	NM_021141.4	P1
XRCC5	ENST00000460284.5	n.1761G>A		non_coding_transcript_exon_variant	8/18	1
XRCC5	ENST00000392133.7	c.1219G>A	p.Val407Met	missense_variant	13/23	5		P1
XRCC5	ENST00000471649.1	n.353G>A		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461162 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.1219G>A (p.V407M) alteration is located in exon 11 (coding exon 11) of the XRCC5 gene. This alteration results from a G to A substitution at nucleotide position 1219, causing the valine (V) at amino acid position 407 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.065
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.070
Sift	Benign	0.11	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.32	B;B
Vest4		0.36
MutPred		0.63		Gain of disorder (P = 0.1723);Gain of disorder (P = 0.1723);
MVP		0.15
MPC		0.95
ClinPred		0.32	T
GERP RS		3.6
Varity_R		0.087
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs866431729; hg19: chr2-217001916;