19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr19-43543341-C-CGTGTGT
• rs45592142
• NM_006297.3:c.*45_*50dupACACAC

Variant summary

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

The NM_006297.3(XRCC1):​c.*45_*50dupACACAC 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 0.0088 (18 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (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 = 0.00879 (1225/139300) while in subpopulation AFR AF = 0.0195 (696/35684). AF 95% confidence interval is 0.0183. There are 18 homozygotes in GnomAd4. There are 583 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1225 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_*50dupACACAC		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.*45_*50dupACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*45_*50dupACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*45_*50dupACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1223 AN: 139198 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00997

Gnomad ASJ AF: 0.00385

Gnomad EAS AF: 0.00910

Gnomad SAS AF: 0.000928

Gnomad FIN AF: 0.00953

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00793

GnomAD4 exome AF: 0.00320 AC: 2890 AN: 904314 Hom.: 2 Cov.: 0 AF XY: 0.00310 AC XY: 1441 AN XY: 465314

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

African (AFR) AF: 0.0157 AC: 327 AN: 20762

American (AMR) AF: 0.00885 AC: 332 AN: 37530

Ashkenazi Jewish (ASJ) AF: 0.00307 AC: 63 AN: 20506

East Asian (EAS) AF: 0.00852 AC: 305 AN: 35818

South Asian (SAS) AF: 0.00236 AC: 166 AN: 70400

European-Finnish (FIN) AF: 0.00716 AC: 284 AN: 39690

Middle Eastern (MID) AF: 0.00461 AC: 18 AN: 3902

European-Non Finnish (NFE) AF: 0.00197 AC: 1248 AN: 634424

Other (OTH) AF: 0.00356 AC: 147 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: 0.00879 AC: 1225 AN: 139300 Hom.: 18 Cov.: 0 AF XY: 0.00866 AC XY: 583 AN XY: 67310

African (AFR) AF: 0.0195 AC: 696 AN: 35684

American (AMR) AF: 0.00988 AC: 136 AN: 13768

Ashkenazi Jewish (ASJ) AF: 0.00385 AC: 13 AN: 3380

East Asian (EAS) AF: 0.00913 AC: 43 AN: 4712

South Asian (SAS) AF: 0.000929 AC: 4 AN: 4304

European-Finnish (FIN) AF: 0.00953 AC: 85 AN: 8922

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00354 AC: 232 AN: 65450

Other (OTH) AF: 0.00786 AC: 15 AN: 1908

Alfa AF: 0.00157 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

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;