chr22-41663764-G-T

Variant names:

• chr22-41663764-G-T
• rs132788
• NM_001469.5:c.1779G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001469.5(XRCC6):​c.1779G>T​(p.Gly593Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,588 control chromosomes in the GnomAD database, including 91,680 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6315 hom., cov: 32)
  • Exomes 𝑓: 0.34 (85365 hom.)
• Consequence: XRCC6 NM_001469.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 37 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC6	NM_001469.5	MANE Select	c.1779G>T	p.Gly593Gly	synonymous	Exon 13 of 13	NP_001460.1
	XRCC6	NM_001288976.2		c.1779G>T	p.Gly593Gly	synonymous	Exon 13 of 13	NP_001275905.1
	XRCC6	NM_001288977.2		c.1656G>T	p.Gly552Gly	synonymous	Exon 13 of 13	NP_001275906.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC6	ENST00000360079.8	TSL:1 MANE Select	c.1779G>T	p.Gly593Gly	synonymous	Exon 13 of 13	ENSP00000353192.3
	XRCC6	ENST00000359308.8	TSL:1	c.1779G>T	p.Gly593Gly	synonymous	Exon 12 of 12	ENSP00000352257.4
	XRCC6	ENST00000405878.5	TSL:5	c.1779G>T	p.Gly593Gly	synonymous	Exon 13 of 13	ENSP00000384257.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39673 AN: 152040 Hom.: 6307 Cov.: 32

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.296

GnomAD2 exomes AF: 0.290 AC: 72679 AN: 250882 AF XY: 0.297

Gnomad AFR exome AF: 0.0774

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.336 AC: 490730 AN: 1461430 Hom.: 85365 Cov.: 51 AF XY: 0.334 AC XY: 242925 AN XY: 727042

African (AFR) AF: 0.0721 AC: 2412 AN: 33468

American (AMR) AF: 0.183 AC: 8182 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 7425 AN: 26130

East Asian (EAS) AF: 0.249 AC: 9887 AN: 39700

South Asian (SAS) AF: 0.253 AC: 21832 AN: 86244

European-Finnish (FIN) AF: 0.335 AC: 17879 AN: 53412

Middle Eastern (MID) AF: 0.311 AC: 1747 AN: 5626

European-Non Finnish (NFE) AF: 0.361 AC: 401891 AN: 1111792

Other (OTH) AF: 0.323 AC: 19475 AN: 60344

GnomAD4 genome AF: 0.261 AC: 39678 AN: 152158 Hom.: 6315 Cov.: 32 AF XY: 0.258 AC XY: 19228 AN XY: 74384

African (AFR) AF: 0.0838 AC: 3482 AN: 41550

American (AMR) AF: 0.242 AC: 3704 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3468

East Asian (EAS) AF: 0.246 AC: 1269 AN: 5168

South Asian (SAS) AF: 0.243 AC: 1175 AN: 4828

European-Finnish (FIN) AF: 0.339 AC: 3592 AN: 10582

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24500 AN: 67966

Other (OTH) AF: 0.303 AC: 638 AN: 2106

Alfa AF: 0.283 Hom.: 3047

Bravo AF: 0.246

Asia WGS AF: 0.297 AC: 1031 AN: 3478

EpiCase AF: 0.352

EpiControl AF: 0.364

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.1
DANN	Benign	0.86
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

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

dbSNP: rs132788; hg19: chr22-42059768; COSMIC: COSV63752372; COSMIC: COSV63752372;