2-216138116-A-C

Position:

• chr2-216138116-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000392132.7(XRCC5):​c.1279A>C​(p.Met427Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC5 ENST00000392132.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC5	NM_021141.4	c.1279A>C	p.Met427Leu	missense_variant	12/21	ENST00000392132.7	NP_066964.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC5	ENST00000392132.7	c.1279A>C	p.Met427Leu	missense_variant	12/21	1	NM_021141.4	ENSP00000375977	P1
XRCC5	ENST00000460284.5	n.1821A>C		non_coding_transcript_exon_variant	9/18	1
XRCC5	ENST00000392133.7	c.1279A>C	p.Met427Leu	missense_variant	14/23	5		ENSP00000375978	P1
XRCC5	ENST00000471649.1	n.413A>C		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 23, 2024

The c.1279A>C (p.M427L) alteration is located in exon 12 (coding exon 12) of the XRCC5 gene. This alteration results from a A to C substitution at nucleotide position 1279, causing the methionine (M) at amino acid position 427 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.92	P;P
Vest4		0.54
MutPred		0.73		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.32
MPC		1.0
ClinPred		0.94	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1697117570; hg19: chr2-217002839;