chr22-41636742-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

XRCC6 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001469.5. 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
	XRCC6	NM_001469.5	MANE Select	c.561G>T	p.Arg187Ser	missense	Exon 5 of 13	NP_001460.1	P12956-1
	XRCC6	NM_001288976.2		c.561G>T	p.Arg187Ser	missense	Exon 5 of 13	NP_001275905.1	P12956-1
	XRCC6	NM_001288977.2		c.438G>T	p.Arg146Ser	missense	Exon 5 of 13	NP_001275906.1	P12956-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC6	ENST00000360079.8	TSL:1 MANE Select	c.561G>T	p.Arg187Ser	missense	Exon 5 of 13	ENSP00000353192.3	P12956-1
	XRCC6	ENST00000359308.8	TSL:1	c.561G>T	p.Arg187Ser	missense	Exon 4 of 12	ENSP00000352257.4	P12956-1
	XRCC6	ENST00000938034.1		c.561G>T	p.Arg187Ser	missense	Exon 5 of 14	ENSP00000608093.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.29
Sift	Benign	0.051	T
Sift4G	Benign	0.062	T
Polyphen		0.17	B
Vest4		0.78
MutPred		0.54		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
Mutation Taster		=16/84	disease causing

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

hg19: chr22-42032746;