19-43554989-G-T

Variant names:

• chr19-43554989-G-T
• rs1799778
• NM_006297.3:c.256-185C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105
• Publications: 20 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)

ENSG00000268361 (HGNC:):

ACMG classification

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.

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.256-185C>A		intron	N/A	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.256-185C>A		intron	N/A	ENSP00000262887.5	P18887
	ENSG00000268361	ENST00000594374.1	TSL:3	c.280-185C>A		intron	N/A	ENSP00000472698.1	M0R2N6
	XRCC1	ENST00000953258.1		c.256-185C>A		intron	N/A	ENSP00000623317.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47092 AN: 151824 Hom.: 7518 Cov.: 31

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.: 5 AF XY: 0.342 AC XY: 64258 AN XY: 187640

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

GnomAD4 genome AF: 0.310 AC: 47121 AN: 151942 Hom.: 7529 Cov.: 31 AF XY: 0.307 AC XY: 22783 AN XY: 74274

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: 78 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24325 AN: 67936

Other (OTH) AF: 0.308 AC: 650 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.96
DANN	Benign	0.83
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799778; hg19: chr19-44059141; COSMIC: COSV53450734; COSMIC: COSV53450734;