19-43543673-T-G

Variant names:

• chr19-43543673-T-G
• rs2307177
• NM_006297.3:c.1727A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006297.3(XRCC1):​c.1727A>C​(p.Tyr576Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0123 in 1,613,906 control chromosomes in the GnomAD database, including 198 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y576C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 30)
  • Exomes 𝑓: 0.012 (156 hom.)
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007240653).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0195 (2959/152036) while in subpopulation AFR AF = 0.0378 (1567/41428). AF 95% confidence interval is 0.0363. There are 42 homozygotes in GnomAd4. There are 1402 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2959 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.1727A>C	p.Tyr576Ser	missense	Exon 16 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.1727A>C	p.Tyr576Ser	missense	Exon 16 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.1739A>C	p.Tyr580Ser	missense	Exon 16 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.1724A>C	p.Tyr575Ser	missense	Exon 16 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2954 AN: 151918 Hom.: 42 Cov.: 30

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0123 AC: 3100 AN: 251426 AF XY: 0.0126

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0116 AC: 16921 AN: 1461870 Hom.: 156 Cov.: 34 AF XY: 0.0116 AC XY: 8440 AN XY: 727240

African (AFR) AF: 0.0424 AC: 1421 AN: 33480

American (AMR) AF: 0.0132 AC: 591 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 503 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0148 AC: 1279 AN: 86258

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53418

Middle Eastern (MID) AF: 0.0463 AC: 267 AN: 5766

European-Non Finnish (NFE) AF: 0.0106 AC: 11841 AN: 1112002

Other (OTH) AF: 0.0157 AC: 947 AN: 60394

GnomAD4 genome AF: 0.0195 AC: 2959 AN: 152036 Hom.: 42 Cov.: 30 AF XY: 0.0189 AC XY: 1402 AN XY: 74312

African (AFR) AF: 0.0378 AC: 1567 AN: 41428

American (AMR) AF: 0.0233 AC: 356 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.0148 AC: 71 AN: 4812

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10594

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 826 AN: 68000

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.0138 Hom.: 68

Bravo AF: 0.0225

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.0125 AC: 1514

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0027
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0072	T
PhyloP100		6.1
Sift4G	Benign	0.11	T
Vest4		0.53
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.69
Mutation Taster		=97/3	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: rs2307177; hg19: chr19-44047825;