22-41636742-G-T

Variant names:

• chr22-41636742-G-T
• NM_001469.5:c.561G>T

Variant summary

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

The NM_001469.5(XRCC6):​c.561G>T​(p.Arg187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: XRCC6 NM_001469.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

XRCC6 (HGNC:4055): (X-ray repair cross complementing 6) The p70/p80 autoantigen is a nuclear complex consisting of two subunits with molecular masses of approximately 70 and 80 kDa. The complex functions as a single-stranded DNA-dependent ATP-dependent helicase. The complex may be involved in the repair of nonhomologous DNA ends such as that required for double-strand break repair, transposition, and V(D)J recombination. High levels of autoantibodies to p70 and p80 have been found in some patients with systemic lupus erythematosus. [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 rank	MANE	Protein	UniProt
XRCC6	NM_001469.5	c.561G>T	p.Arg187Ser	missense_variant	Exon 5 of 13	ENST00000360079.8	NP_001460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC6	ENST00000360079.8	c.561G>T	p.Arg187Ser	missense_variant	Exon 5 of 13	1	NM_001469.5	ENSP00000353192.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.561G>T (p.R187S) alteration is located in exon 5 (coding exon 4) of the XRCC6 gene. This alteration results from a G to T substitution at nucleotide position 561, causing the arginine (R) at amino acid position 187 to be replaced by a serine (S). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.;T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	.;D;D;.;D;.
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.;.;M;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;.;D;D;D;D
REVEL	Benign	0.29
Sift	Benign	0.051	T;.;T;T;T;T
Sift4G	Benign	0.062	T;T;T;T;T;T
Polyphen		0.17	B;B;.;B;B;B
Vest4		0.78
MutPred		0.54		Gain of phosphorylation at R187 (P = 0.0149);.;.;Gain of phosphorylation at R187 (P = 0.0149);Gain of phosphorylation at R187 (P = 0.0149);.;
MVP		0.40
MPC		1.3
ClinPred		0.97	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.77
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42032746;