rs1044999002

Variant names:

• chr19-43544199-C-T
• rs1044999002
• NM_006297.3:c.1657G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006297.3(XRCC1):​c.1657G>A​(p.Glu553Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25843623).

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.1657G>A	p.Glu553Lys	missense	Exon 15 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.1657G>A	p.Glu553Lys	missense	Exon 15 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.1669G>A	p.Glu557Lys	missense	Exon 15 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.1654G>A	p.Glu552Lys	missense	Exon 15 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458896 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725280

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110762

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.65	T
PhyloP100		3.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.33
Sift	Benign	0.34	T
Sift4G	Benign	0.60	T
Polyphen		0.090	B
Vest4		0.39
MutPred		0.52		Gain of methylation at E553 (P = 0.0071)
MVP		0.59
MPC		0.57
ClinPred		0.64	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.38
Mutation Taster		=93/7	polymorphism

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: rs1044999002; hg19: chr19-44048351; COSMIC: COSV53453790;