22-41636188-G-C

Variant names:

• chr22-41636188-G-C
• rs373148769
• NM_001469.5:c.271G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001469.5(XRCC6):​c.271G>C​(p.Glu91Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E91K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC6 NM_001469.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.813

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15088272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC6	NM_001469.5	c.271G>C	p.Glu91Gln	missense_variant	Exon 4 of 13	ENST00000360079.8	NP_001460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC6	ENST00000360079.8	c.271G>C	p.Glu91Gln	missense_variant	Exon 4 of 13	1	NM_001469.5	ENSP00000353192.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T;T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	.;D;.;D;.
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;.;M;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N;.;N;N;N
REVEL	Benign	0.076
Sift	Uncertain	0.016	D;.;D;D;D
Sift4G	Benign	0.087	T;T;T;T;T
Polyphen		0.25	B;B;B;B;B
Vest4		0.095
MutPred		0.52		Loss of ubiquitination at K94 (P = 0.0381);.;Loss of ubiquitination at K94 (P = 0.0381);Loss of ubiquitination at K94 (P = 0.0381);.;
MVP		0.093
MPC		1.0
ClinPred		0.21	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs373148769; hg19: chr22-42032192;