Genetic Variant XRCC1:c.*41_*50dupACACACACAC (chr19-43543341-C-CGTGTGTGTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006297.3(XRCC1):c.*41_*50dupACACACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0088 ( 22 hom., cov: 0)

Exomes 𝑓: 0.0031 ( 4 hom. )

Consequence

XRCC1
NM_006297.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.110

Publications

2 publications found

Variant links:

Genes affected

XRCC1 (HGNC:12828): (X-ray repair cross complementing 1) The protein encoded by this gene is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. This protein interacts with DNA ligase III, polymerase beta and poly (ADP-ribose) polymerase to participate in the base excision repair pathway. It may play a role in DNA processing during meiogenesis and recombination in germ cells. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. [provided by RefSeq, Jul 2008]

XRCC1 Gene-Disease associations (from GenCC):

head and neck cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
spinocerebellar ataxia, autosomal recessive 26
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

XRCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 1222 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006297.3. 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
	XRCC1	NM_006297.3	MANE Select	c.41_50dupACACACACAC		3_prime_UTR	Exon 17 of 17	NP_006288.2	P18887

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.41_50dupACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
XRCC1	ENST00000953258.1		c.41_50dupACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
XRCC1	ENST00000865401.1		c.41_50dupACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes

AF:

0.00877

AC:

1221

AN:

139196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0137

Gnomad AMI

AF:

0.0258

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.000212

Gnomad SAS

AF:

0.00719

Gnomad FIN

AF:

0.000784

Gnomad MID

AF:

0.0232

Gnomad NFE

AF:

0.00765

Gnomad OTH

AF:

0.0100

GnomAD4 exome

AF:

0.00309

AC:

2791

AN:

904232

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

1524

AN XY:

465224

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00763

AC:

159

AN:

20842

American (AMR)

AF:

0.00396

AC:

149

AN:

37582

Ashkenazi Jewish (ASJ)

AF:

0.00728

AC:

149

AN:

20460

East Asian (EAS)

AF:

0.000111

AC:

AN:

35912

South Asian (SAS)

AF:

0.00452

AC:

318

AN:

70362

European-Finnish (FIN)

AF:

0.000730

AC:

AN:

39752

Middle Eastern (MID)

AF:

0.0159

AC:

AN:

3892

European-Non Finnish (NFE)

AF:

0.00273

AC:

1729

AN:

634150

Other (OTH)

AF:

0.00465

AC:

192

AN:

41280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.373

Heterozygous variant carriers

139

279

418

558

697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00877

AC:

1222

AN:

139298

Hom.:

Cov.:

AF XY:

0.00905

AC XY:

609

AN XY:

67300

show subpopulations

African (AFR)

AF:

0.0137

AC:

490

AN:

35688

American (AMR)

AF:

0.00719

AC:

AN:

13768

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3380

East Asian (EAS)

AF:

0.000212

AC:

AN:

4712

South Asian (SAS)

AF:

0.00720

AC:

AN:

4304

European-Finnish (FIN)

AF:

0.000784

AC:

AN:

8924

Middle Eastern (MID)

AF:

0.0177

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00767

AC:

502

AN:

65440

Other (OTH)

AF:

0.00995

AC:

AN:

1910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over