Genetic Variant NM_006297.3:c.256-185C>A (chr19-43554989-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006297.3(XRCC1):c.256-185C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 512,484 control chromosomes in the GnomAD database, including 29,002 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7529 hom., cov: 31)

Exomes 𝑓: 0.34 ( 21473 hom. )

Consequence

XRCC1
NM_006297.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.105

Publications

20 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:

ENSG00000268361 (HGNC:):

ENSG00000268361 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3 link	c.256-185C>A		intron_variant	Intron 3 of 16	ENST00000262887.10	NP_006288.2	P18887B2RCY5Q59HH7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10 link	c.256-185C>A		intron_variant	Intron 3 of 16	1	NM_006297.3	ENSP00000262887.5		P18887
ENSG00000268361	ENST00000594374.1 link	c.280-185C>A		intron_variant	Intron 2 of 2	3		ENSP00000472698.1		M0R2N6

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47092

AN:

151824

Hom.:

7518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.412

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.425

Gnomad EAS

AF:

0.263

Gnomad SAS

AF:

0.348

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.358

Gnomad OTH

AF:

0.306

GnomAD4 exome

AF:

0.340

AC:

122496

AN:

360542

Hom.:

21473

Cov.:

AF XY:

0.342

AC XY:

64258

AN XY:

187640

show subpopulations

African (AFR)

AF:

0.219

AC:

2175

AN:

9946

American (AMR)

AF:

0.293

AC:

3558

AN:

12154

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

4456

AN:

11018

East Asian (EAS)

AF:

0.255

AC:

6476

AN:

25440

South Asian (SAS)

AF:

0.353

AC:

8956

AN:

25402

European-Finnish (FIN)

AF:

0.313

AC:

7530

AN:

24054

Middle Eastern (MID)

AF:

0.312

AC:

524

AN:

1680

European-Non Finnish (NFE)

AF:

0.356

AC:

81923

AN:

230042

Other (OTH)

AF:

0.332

AC:

6898

AN:

20806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

3769

7538

11307

15076

18845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

872

1744

2616

3488

4360

<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:

0.310

AC:

47121

AN:

151942

Hom.:

7529

Cov.:

AF XY:

0.307

AC XY:

22783

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.220

AC:

9120

AN:

41440

American (AMR)

AF:

0.319

AC:

4869

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.425

AC:

1473

AN:

3466

East Asian (EAS)

AF:

0.263

AC:

1356

AN:

5158

South Asian (SAS)

AF:

0.348

AC:

1676

AN:

4812

European-Finnish (FIN)

AF:

0.303

AC:

3203

AN:

10568

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.358

AC:

24325

AN:

67936

Other (OTH)

AF:

0.308

AC:

650

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1650

3301

4951

6602

8252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.328

Hom.:

4320

Bravo

AF:

0.305

Asia WGS

AF:

0.296

AC:

1029

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.96

(source)

DANN

Benign

0.83

PhyloP100

-0.10

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over