22-41621260-A-G

Variant names:

• chr22-41621260-A-G
• rs132770
• ENST00000938029.1:c.-101A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000428575.6(XRCC6):​c.-138A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 230,902 control chromosomes in the GnomAD database, including 78,218 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 0.83 (53445 hom., cov: 31)
  • Exomes 𝑓: 0.79 (24773 hom.)
• Consequence: XRCC6 ENST00000428575.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.63
• 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]

DESI1 (HGNC:24577): (desumoylating isopeptidase 1) Enables importin-alpha family protein binding activity. Involved in protein export from nucleus and regulation of proteasomal ubiquitin-dependent protein catabolic process. Located in cytosol. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000428575.6. 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.-101A>G		upstream_gene	N/A	NP_001460.1	P12956-1
	DESI1	NM_015704.3	MANE Select	c.-421T>C		upstream_gene	N/A	NP_056519.1	Q6ICB0
	XRCC6	NM_001288976.2		c.-166A>G		upstream_gene	N/A	NP_001275905.1	P12956-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC6	ENST00000938029.1		c.-101A>G		5_prime_UTR	Exon 1 of 13	ENSP00000608088.1
	XRCC6	ENST00000428575.6	TSL:2	c.-138A>G		5_prime_UTR	Exon 1 of 12	ENSP00000403679.3	B1AHC9
	XRCC6	ENST00000938028.1		c.-16+228A>G		intron	N/A	ENSP00000608087.1

Frequencies

GnomAD3 genomes AF: 0.830 AC: 126218 AN: 152002 Hom.: 53383 Cov.: 31

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.941

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.801

GnomAD4 exome AF: 0.787 AC: 62027 AN: 78782 Hom.: 24773 Cov.: 0 AF XY: 0.778 AC XY: 32422 AN XY: 41662

African (AFR) AF: 0.945 AC: 1399 AN: 1480

American (AMR) AF: 0.562 AC: 1469 AN: 2612

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 1588 AN: 2212

East Asian (EAS) AF: 0.952 AC: 3169 AN: 3330

South Asian (SAS) AF: 0.698 AC: 6729 AN: 9644

European-Finnish (FIN) AF: 0.747 AC: 4428 AN: 5924

Middle Eastern (MID) AF: 0.737 AC: 264 AN: 358

European-Non Finnish (NFE) AF: 0.810 AC: 39441 AN: 48718

Other (OTH) AF: 0.786 AC: 3540 AN: 4504

GnomAD4 genome AF: 0.830 AC: 126335 AN: 152120 Hom.: 53445 Cov.: 31 AF XY: 0.821 AC XY: 61063 AN XY: 74356

African (AFR) AF: 0.955 AC: 39644 AN: 41530

American (AMR) AF: 0.642 AC: 9808 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 2515 AN: 3468

East Asian (EAS) AF: 0.942 AC: 4849 AN: 5148

South Asian (SAS) AF: 0.701 AC: 3384 AN: 4824

European-Finnish (FIN) AF: 0.762 AC: 8057 AN: 10578

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55512 AN: 67982

Other (OTH) AF: 0.804 AC: 1697 AN: 2112

Alfa AF: 0.817 Hom.: 14846

Bravo AF: 0.824

Asia WGS AF: 0.844 AC: 2937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.088
DANN	Benign	0.76
PhyloP100		-3.6
PromoterAI		-0.060	Neutral
Mutation Taster		=300/0	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: rs132770; hg19: chr22-42017264; COSMIC: COSV54354414;