22-41637686-T-C

Position:

• chr22-41637686-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001469.5(XRCC6):​c.668T>C​(p.Ile223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: XRCC6 NM_001469.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.367

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 Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.024856418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC6	NM_001469.5	c.668T>C	p.Ile223Thr	missense_variant	6/13	ENST00000360079.8	NP_001460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC6	ENST00000360079.8	c.668T>C	p.Ile223Thr	missense_variant	6/13	1	NM_001469.5	ENSP00000353192	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461118 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726812

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: 0.00

GnomAD4 genome Cov.: 30

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

Aug 14, 2023

The c.668T>C (p.I223T) alteration is located in exon 6 (coding exon 5) of the XRCC6 gene. This alteration results from a T to C substitution at nucleotide position 668, causing the isoleucine (I) at amino acid position 223 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.15	T;T;.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.87	.;D;D;.;D;.
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.025	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N;.;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.29	N;.;N;N;N;N
REVEL	Benign	0.099
Sift	Benign	0.59	T;.;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B
Vest4		0.032
MutPred		0.49		Loss of stability (P = 0.0201);.;.;Loss of stability (P = 0.0201);Loss of stability (P = 0.0201);.;
MVP		0.043
MPC		0.96
ClinPred		0.023	T
GERP RS		-0.67
Varity_R		0.076
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2067823968; hg19: chr22-42033690;