rs2295475

Variant names:

• chr2-31366981-G-A
• rs2295475
• NM_000379.4:c.2211C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000379.4(XDH):​c.2211C>T​(p.Ile737Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,614,036 control chromosomes in the GnomAD database, including 74,844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5554 hom., cov: 34)
  • Exomes 𝑓: 0.30 (69290 hom.)
• Consequence: XDH NM_000379.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.294

Genes affected

XDH (HGNC:12805): (xanthine dehydrogenase) Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Xanthine dehydrogenase can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification. Defects in xanthine dehydrogenase cause xanthinuria, may contribute to adult respiratory stress syndrome, and may potentiate influenza infection through an oxygen metabolite-dependent mechanism. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-31366981-G-A is Benign according to our data. Variant chr2-31366981-G-A is described in ClinVar as [Benign]. Clinvar id is 255967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31366981-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.294 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.2211C>T	p.Ile737Ile	synonymous_variant	Exon 21 of 36	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.2208C>T	p.Ile736Ile	synonymous_variant	Exon 21 of 36		XP_011531397.1
XDH	XM_011533096.3	c.2211C>T	p.Ile737Ile	synonymous_variant	Exon 21 of 29		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.2211C>T	p.Ile737Ile	synonymous_variant	Exon 21 of 36	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38007 AN: 152120 Hom.: 5554 Cov.: 34

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.249

GnomAD3 exomes AF: 0.309 AC: 77569 AN: 251432 Hom.: 12720 AF XY: 0.310 AC XY: 42070 AN XY: 135874

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.342

Gnomad SAS exome AF: 0.350

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.304 AC: 444675 AN: 1461796 Hom.: 69290 Cov.: 52 AF XY: 0.306 AC XY: 222484 AN XY: 727184

Gnomad4 AFR exome AF: 0.0755

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.250 AC: 38002 AN: 152240 Hom.: 5554 Cov.: 34 AF XY: 0.254 AC XY: 18933 AN XY: 74420

Gnomad4 AFR AF: 0.0878

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.250

Alfa AF: 0.293 Hom.: 15009

Bravo AF: 0.242

Asia WGS AF: 0.360 AC: 1251 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.297

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary xanthinuria type 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xanthinuria type II Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.015
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2295475; hg19: chr2-31589847; COSMIC: COSV65147622;