22-41650817-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001469.5(XRCC6):​c.1055C>T​(p.Pro352Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P352Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

XRCC6
NM_001469.5 missense

Scores

8
9
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.31
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XRCC6NM_001469.5 linkc.1055C>T p.Pro352Leu missense_variant Exon 8 of 13 ENST00000360079.8 NP_001460.1 P12956-1A0A024R1N4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XRCC6ENST00000360079.8 linkc.1055C>T p.Pro352Leu missense_variant Exon 8 of 13 1 NM_001469.5 ENSP00000353192.3 P12956-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461724
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;T;.;D;D;T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
.;D;D;.;D;.
M_CAP
Benign
0.057
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Pathogenic
3.6
H;.;.;H;H;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-8.8
D;.;D;D;D;D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0010
D;.;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;D;D
Vest4
0.86
MutPred
0.82
Loss of methylation at K351 (P = 0.0908);.;.;Loss of methylation at K351 (P = 0.0908);Loss of methylation at K351 (P = 0.0908);.;
MVP
0.39
MPC
1.8
ClinPred
1.0
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.85
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42046821; COSMIC: COSV63158731; COSMIC: COSV63158731; API