19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr19-43543341-C-CGTGTGTGT
• rs45592142
• NM_006297.3:c.*43_*50dupACACACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_006297.3(XRCC1):​c.*43_*50dupACACACAC 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 0.0087 (22 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (2 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00866 (1207/139310) while in subpopulation AFR AF = 0.0272 (972/35686). AF 95% confidence interval is 0.0258. There are 22 homozygotes in GnomAd4. There are 570 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1207 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.*43_*50dupACACACAC		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.*43_*50dupACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*43_*50dupACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*43_*50dupACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1205 AN: 139208 Hom.: 22 Cov.: 0

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000846

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00142

Gnomad OTH AF: 0.00739

GnomAD4 exome AF: 0.00175 AC: 1584 AN: 904314 Hom.: 2 Cov.: 0 AF XY: 0.00168 AC XY: 781 AN XY: 465302

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

African (AFR) AF: 0.0176 AC: 366 AN: 20760

American (AMR) AF: 0.00346 AC: 130 AN: 37562

Ashkenazi Jewish (ASJ) AF: 0.00166 AC: 34 AN: 20474

East Asian (EAS) AF: 0.00131 AC: 47 AN: 35884

South Asian (SAS) AF: 0.00166 AC: 117 AN: 70378

European-Finnish (FIN) AF: 0.000176 AC: 7 AN: 39748

Middle Eastern (MID) AF: 0.00590 AC: 23 AN: 3896

European-Non Finnish (NFE) AF: 0.00117 AC: 742 AN: 634330

Other (OTH) AF: 0.00286 AC: 118 AN: 41282

⚠️ 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: 0.00866 AC: 1207 AN: 139310 Hom.: 22 Cov.: 0 AF XY: 0.00847 AC XY: 570 AN XY: 67310

African (AFR) AF: 0.0272 AC: 972 AN: 35686

American (AMR) AF: 0.00850 AC: 117 AN: 13770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.000849 AC: 4 AN: 4712

South Asian (SAS) AF: 0.00116 AC: 5 AN: 4304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8924

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.00142 AC: 93 AN: 65452

Other (OTH) AF: 0.00733 AC: 14 AN: 1910

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

Other links and lift over

dbSNP: rs45592142; hg19: chr19-44047493;