NM_006297.3:c.*39_*50dupACACACACACAC

Variant names:

• chr19-43543341-C-CGTGTGTGTGTGT
• rs45592142
• NM_006297.3:c.*39_*50dupACACACACACAC

Variant summary

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

The NM_006297.3(XRCC1):​c.*39_*50dupACACACACACAC 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 0.0031 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 437 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.*39_*50dupACACACACACAC		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.*39_*50dupACACACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*39_*50dupACACACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*39_*50dupACACACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 437 AN: 139210 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00464

Gnomad FIN AF: 0.000224

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.00289

Gnomad OTH AF: 0.00264

GnomAD4 exome AF: 0.00106 AC: 961 AN: 904890 Hom.: 0 Cov.: 0 AF XY: 0.00121 AC XY: 562 AN XY: 465622

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

African (AFR) AF: 0.00206 AC: 43 AN: 20864

American (AMR) AF: 0.00186 AC: 70 AN: 37604

Ashkenazi Jewish (ASJ) AF: 0.000975 AC: 20 AN: 20508

East Asian (EAS) AF: 0.00 AC: 0 AN: 35914

South Asian (SAS) AF: 0.00301 AC: 212 AN: 70400

European-Finnish (FIN) AF: 0.000126 AC: 5 AN: 39764

Middle Eastern (MID) AF: 0.00179 AC: 7 AN: 3900

European-Non Finnish (NFE) AF: 0.000862 AC: 547 AN: 634614

Other (OTH) AF: 0.00138 AC: 57 AN: 41322

⚠️ 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: 0.00314 AC: 437 AN: 139312 Hom.: 2 Cov.: 0 AF XY: 0.00303 AC XY: 204 AN XY: 67314

African (AFR) AF: 0.00429 AC: 153 AN: 35698

American (AMR) AF: 0.00479 AC: 66 AN: 13770

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4712

South Asian (SAS) AF: 0.00465 AC: 20 AN: 4300

European-Finnish (FIN) AF: 0.000224 AC: 2 AN: 8924

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

European-Non Finnish (NFE) AF: 0.00289 AC: 189 AN: 65446

Other (OTH) AF: 0.00262 AC: 5 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
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;