22-41653559-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_StrongBP6_Moderate

The NM_001469.5(XRCC6):ā€‹c.1160T>Cā€‹(p.Ile387Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I387L) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

XRCC6
NM_001469.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.726
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), XRCC6. . Gene score misZ 3.0983 (greater than the threshold 3.09). Trascript score misZ 4.177 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.
BP4
Computational evidence support a benign effect (MetaRNN=0.045337886).
BP6
Variant 22-41653559-T-C is Benign according to our data. Variant chr22-41653559-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2302805.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
XRCC6NM_001469.5 linkuse as main transcriptc.1160T>C p.Ile387Thr missense_variant 9/13 ENST00000360079.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
XRCC6ENST00000360079.8 linkuse as main transcriptc.1160T>C p.Ile387Thr missense_variant 9/131 NM_001469.5 P1P12956-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152200
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251380
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461360
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726966
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:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152200
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 20, 2022This 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
0.076
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
13
DANN
Benign
0.80
DEOGEN2
Benign
0.15
T;T;.;T;T;T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.80
.;T;T;.;T;.
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.045
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.3
N;.;.;N;N;.
MutationTaster
Benign
0.96
N;N;N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
1.1
N;.;N;N;N;N
REVEL
Benign
0.0080
Sift
Benign
0.70
T;.;T;T;T;T
Sift4G
Benign
0.91
T;T;T;T;T;T
Polyphen
0.0
B;B;.;B;B;B
Vest4
0.13
MutPred
0.39
Loss of stability (P = 0.0023);.;.;Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);.;
MVP
0.043
MPC
0.96
ClinPred
0.029
T
GERP RS
1.8
Varity_R
0.091
gMVP
0.57

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.

Other links and lift over

dbSNP: rs758500661; hg19: chr22-42049563; API