Genetic Variant XRCC6:c.-138A>G (chr22-41621260-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000428575(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 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.63

Variant links:

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 links:

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]

DESI1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC6	NM_001469.5 link	c.-101A>G		upstream_gene_variant		ENST00000360079.8	NP_001460.1	P12956-1A0A024R1N4
DESI1	NM_015704.3 link	c.-421T>C		upstream_gene_variant		ENST00000263256.7	NP_056519.1	Q6ICB0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC6	ENST00000360079.8 link	c.-101A>G		upstream_gene_variant		1	NM_001469.5	ENSP00000353192.3		P12956-1
DESI1	ENST00000263256.7 link	c.-421T>C		upstream_gene_variant		1	NM_015704.3	ENSP00000263256.6		Q6ICB0

Frequencies

GnomAD3 genomes

AF:

0.830

AC:

126218

AN:

152002

Hom.:

53383

Cov.:

show subpopulations

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.:

AF XY:

0.778

AC XY:

32422

AN XY:

41662

show subpopulations

Gnomad4 AFR exome

AF:

0.945

Gnomad4 AMR exome

AF:

0.562

Gnomad4 ASJ exome

AF:

0.718

Gnomad4 EAS exome

AF:

0.952

Gnomad4 SAS exome

AF:

0.698

Gnomad4 FIN exome

AF:

0.747

Gnomad4 NFE exome

AF:

0.810

Gnomad4 OTH exome

AF:

0.786

GnomAD4 genome

AF:

0.830

AC:

126335

AN:

152120

Hom.:

53445

Cov.:

AF XY:

0.821

AC XY:

61063

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.955

Gnomad4 AMR

AF:

0.642

Gnomad4 ASJ

AF:

0.725

Gnomad4 EAS

AF:

0.942

Gnomad4 SAS

AF:

0.701

Gnomad4 FIN

AF:

0.762

Gnomad4 NFE

AF:

0.817

Gnomad4 OTH

AF:

0.804

Alfa

AF:

0.816

Hom.:

10985

Bravo

AF:

0.824

Asia WGS

AF:

0.844

AC:

2937

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.088

DANN

Benign

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over