Genetic Variant ENST00000262887:c.*37_*50dupACACACACACACAC (chr19-43543341-C-CGTGTGTGTGTGTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The ENST00000262887.10(XRCC1):c.*37_*50dupACACACACACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

XRCC1
ENST00000262887.10 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 235 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262887.10. 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.37_50dupACACACACACACAC		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.37_50dupACACACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
XRCC1	ENST00000953258.1		c.37_50dupACACACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
XRCC1	ENST00000865401.1		c.37_50dupACACACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

235

AN:

139218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.000212

Gnomad SAS

AF:

0.000232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00993

Gnomad NFE

AF:

0.000703

Gnomad OTH

AF:

0.00370

GnomAD4 exome

AF:

0.000319

AC:

289

AN:

905104

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

147

AN XY:

465720

show subpopulations

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

African (AFR)

AF:

0.00254

AC:

AN:

20854

American (AMR)

AF:

0.000718

AC:

AN:

37610

Ashkenazi Jewish (ASJ)

AF:

0.00137

AC:

AN:

20512

East Asian (EAS)

AF:

0.0000278

AC:

AN:

35914

South Asian (SAS)

AF:

0.000383

AC:

AN:

70434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39768

Middle Eastern (MID)

AF:

0.00102

AC:

AN:

3906

European-Non Finnish (NFE)

AF:

0.000203

AC:

129

AN:

634774

Other (OTH)

AF:

0.000484

AC:

AN:

41332

⚠️ 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: 0.382

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00169

AC:

235

AN:

139320

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

111

AN XY:

67318

show subpopulations

African (AFR)

AF:

0.00328

AC:

117

AN:

35698

American (AMR)

AF:

0.00407

AC:

AN:

13770

Ashkenazi Jewish (ASJ)

AF:

0.00118

AC:

AN:

3380

East Asian (EAS)

AF:

0.000212

AC:

AN:

4712

South Asian (SAS)

AF:

0.000232

AC:

AN:

4304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8924

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000703

AC:

AN:

65450

Other (OTH)

AF:

0.00366

AC:

AN:

1910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00

Hom.:

133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.11

Splicing

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

Publications

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ENST00000262887:c.37_50dupACACACACACACAC

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