22-41650806-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001469.5(XRCC6):c.1044G>A(p.Met348Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: XRCC6 NM_001469.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.375

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, XRCC6
• BP4: Computational evidence support a benign effect (MetaRNN=0.02167952).
• BP6: Variant 22-41650806-G-A is Benign according to our data. Variant chr22-41650806-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2356233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC6	NM_001469.5	c.1044G>A	p.Met348Ile	missense_variant	8/13	ENST00000360079.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC6	ENST00000360079.8	c.1044G>A	p.Met348Ile	missense_variant	8/13	1	NM_001469.5	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251318 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135820

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461690 Hom.: 0 Cov.: 30 AF XY: 0.0000674 AC XY: 49 AN XY: 727154

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.0000671

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: 0.000182

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000510 AC XY: 38 AN XY: 74474

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000699

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	4.4
Dann	Benign	0.89
DEOGEN2	Benign	0.18	T;T;.;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.43	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.022	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N;.;.;N;N;.
MutationTaster	Benign	0.81	D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.83	N;.;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.77	T;.;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;B;B
Vest4		0.27
MutPred		0.46		Loss of ubiquitination at K351 (P = 0.0683);.;.;Loss of ubiquitination at K351 (P = 0.0683);Loss of ubiquitination at K351 (P = 0.0683);.;
MVP		0.082
MPC		0.85
ClinPred		0.0066	T
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144313964; hg19: chr22-42046810;