19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr19-43543341-C-CGT
• rs45592142
• NM_006297.3:c.*49_*50dupAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_006297.3(XRCC1):​c.*49_*50dupAC 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 0.091 (826 hom., cov: 0)
  • Exomes 𝑓: 0.047 (38 hom.)
• Consequence: XRCC1 NM_006297.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

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.*49_*50dupAC		3_prime_UTR	Exon 17 of 17	NP_006288.2	P18887

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.*49_*50dupAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*49_*50dupAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*49_*50dupAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 12710 AN: 139066 Hom.: 830 Cov.: 0

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0619

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0927

Gnomad NFE AF: 0.0625

Gnomad OTH AF: 0.0776

GnomAD4 exome AF: 0.0468 AC: 42064 AN: 898472 Hom.: 38 Cov.: 0 AF XY: 0.0484 AC XY: 22382 AN XY: 462310

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

African (AFR) AF: 0.119 AC: 2470 AN: 20692

American (AMR) AF: 0.0634 AC: 2355 AN: 37162

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 1117 AN: 20316

East Asian (EAS) AF: 0.0362 AC: 1286 AN: 35524

South Asian (SAS) AF: 0.0645 AC: 4503 AN: 69860

European-Finnish (FIN) AF: 0.0379 AC: 1492 AN: 39392

Middle Eastern (MID) AF: 0.0671 AC: 258 AN: 3846

European-Non Finnish (NFE) AF: 0.0418 AC: 26359 AN: 630672

Other (OTH) AF: 0.0542 AC: 2224 AN: 41008

⚠️ 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.

GnomAD4 genome AF: 0.0914 AC: 12722 AN: 139164 Hom.: 826 Cov.: 0 AF XY: 0.0889 AC XY: 5980 AN XY: 67238

African (AFR) AF: 0.183 AC: 6535 AN: 35630

American (AMR) AF: 0.0619 AC: 851 AN: 13746

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 222 AN: 3378

East Asian (EAS) AF: 0.0270 AC: 127 AN: 4712

South Asian (SAS) AF: 0.0814 AC: 350 AN: 4298

European-Finnish (FIN) AF: 0.0304 AC: 271 AN: 8914

Middle Eastern (MID) AF: 0.0816 AC: 23 AN: 282

European-Non Finnish (NFE) AF: 0.0625 AC: 4089 AN: 65404

Other (OTH) AF: 0.0775 AC: 148 AN: 1910

Alfa AF: 0.0514 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 (auto)

Splicing

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

Other links and lift over

dbSNP: rs45592142; hg19: chr19-44047493;