Genetic Variant XRCC6:p.Arg404Lys (chr22-41653610-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001469.5(XRCC6):c.1211G>A(p.Arg404Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. R404M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

XRCC6
NM_001469.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.84

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

XRCC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06488365).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XRCC6	NM_001469.5	MANE Select	c.1211G>A	p.Arg404Lys	missense	Exon 9 of 13	NP_001460.1	P12956-1
XRCC6	NM_001288976.2		c.1211G>A	p.Arg404Lys	missense	Exon 9 of 13	NP_001275905.1	P12956-1
XRCC6	NM_001288977.2		c.1088G>A	p.Arg363Lys	missense	Exon 9 of 13	NP_001275906.1	P12956-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XRCC6	ENST00000360079.8	TSL:1 MANE Select	c.1211G>A	p.Arg404Lys	missense	Exon 9 of 13	ENSP00000353192.3	P12956-1
XRCC6	ENST00000359308.8	TSL:1	c.1211G>A	p.Arg404Lys	missense	Exon 8 of 12	ENSP00000352257.4	P12956-1
XRCC6	ENST00000938034.1		c.1286G>A	p.Arg429Lys	missense	Exon 10 of 14	ENSP00000608093.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.7

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.16

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.75

M_CAP

Benign

0.0024

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

PhyloP100

1.8

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.080

REVEL

Benign

0.12

Sift

Benign

0.87

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.086

MutPred

0.55

Gain of methylation at R404 (P = 0.0058)

MVP

0.093

MPC

0.77

ClinPred

0.034

GERP RS

-0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.80

Mutation Taster

=81/19

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over