22-41636742-G-T

Position:

• chr22-41636742-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), XRCC6. . Gene score misZ 3.0983 (greater than the threshold 3.09). Trascript score misZ 4.177 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC6	NM_001469.5	c.561G>T	p.Arg187Ser	missense_variant	5/13	ENST00000360079.8	NP_001460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC6	ENST00000360079.8	c.561G>T	p.Arg187Ser	missense_variant	5/13	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

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;