Genetic Variant XRCC1:c.*45_*50delACACAC (chr19-43543341-CGTGTGT-C) – 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.*45_*50delACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,037,464 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0012 ( 3 hom., cov: 0)

Exomes 𝑓: 0.024 ( 10 hom. )

Consequence

XRCC1
NM_006297.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.612

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 161 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.45_50delACACAC		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.45_50delACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
XRCC1	ENST00000953258.1		c.45_50delACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
XRCC1	ENST00000865401.1		c.45_50delACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

161

AN:

139160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000509

Gnomad ASJ

AF:

0.000592

Gnomad EAS

AF:

0.000635

Gnomad SAS

AF:

0.000929

Gnomad FIN

AF:

0.00124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000642

Gnomad OTH

AF:

0.000529

GnomAD4 exome

AF:

0.0244

AC:

21875

AN:

898202

Hom.:

AF XY:

0.0247

AC XY:

11434

AN XY:

462066

show subpopulations

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

African (AFR)

AF:

0.0222

AC:

461

AN:

20742

American (AMR)

AF:

0.0112

AC:

419

AN:

37506

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

368

AN:

20378

East Asian (EAS)

AF:

0.0131

AC:

466

AN:

35616

South Asian (SAS)

AF:

0.0281

AC:

1958

AN:

69784

European-Finnish (FIN)

AF:

0.0294

AC:

1153

AN:

39204

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

3890

European-Non Finnish (NFE)

AF:

0.0256

AC:

16109

AN:

630042

Other (OTH)

AF:

0.0218

AC:

895

AN:

41040

⚠️ 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: 0.324

Heterozygous variant carriers

1495

2989

4484

5978

7473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

494

988

1482

1976

2470

<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:

0.00116

AC:

161

AN:

139262

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

67286

show subpopulations

African (AFR)

AF:

0.00255

AC:

AN:

35692

American (AMR)

AF:

0.000508

AC:

AN:

13770

Ashkenazi Jewish (ASJ)

AF:

0.000592

AC:

AN:

3378

East Asian (EAS)

AF:

0.000637

AC:

AN:

4710

South Asian (SAS)

AF:

0.000930

AC:

AN:

4300

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

8894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000642

AC:

AN:

65438

Other (OTH)

AF:

0.000524

AC:

AN:

1908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0140

Hom.:

133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.61

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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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