2-31370399-T-C

Variant names:

• chr2-31370399-T-C
• rs17323225
• NM_000379.4:c.1936A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000379.4(XDH):​c.1936A>G​(p.Ile646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,614,194 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I646K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (58 hom., cov: 33)
  • Exomes 𝑓: 0.031 (798 hom.)
• Consequence: XDH NM_000379.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.77
• Publications: 19 publications found

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]

XDH Gene-Disease associations (from GenCC):

• xanthinuria type I

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021888316).
• BP6: Variant 2-31370399-T-C is Benign according to our data. Variant chr2-31370399-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0227 (3460/152352) while in subpopulation NFE AF = 0.0307 (2091/68034). AF 95% confidence interval is 0.0296. There are 58 homozygotes in GnomAd4. There are 1686 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000379.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.1936A>G	p.Ile646Val	missense	Exon 18 of 36	NP_000370.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.1936A>G	p.Ile646Val	missense	Exon 18 of 36	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3460 AN: 152234 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0251 AC: 6322 AN: 251456 AF XY: 0.0266

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0310

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0307 AC: 44919 AN: 1461842 Hom.: 798 Cov.: 32 AF XY: 0.0307 AC XY: 22327 AN XY: 727222

African (AFR) AF: 0.00556 AC: 186 AN: 33480

American (AMR) AF: 0.0140 AC: 627 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 1250 AN: 26136

East Asian (EAS) AF: 0.000957 AC: 38 AN: 39700

South Asian (SAS) AF: 0.0256 AC: 2209 AN: 86258

European-Finnish (FIN) AF: 0.0308 AC: 1645 AN: 53418

Middle Eastern (MID) AF: 0.0426 AC: 246 AN: 5768

European-Non Finnish (NFE) AF: 0.0332 AC: 36971 AN: 1111962

Other (OTH) AF: 0.0289 AC: 1747 AN: 60396

GnomAD4 genome AF: 0.0227 AC: 3460 AN: 152352 Hom.: 58 Cov.: 33 AF XY: 0.0226 AC XY: 1686 AN XY: 74506

African (AFR) AF: 0.00628 AC: 261 AN: 41582

American (AMR) AF: 0.0250 AC: 383 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 193 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5194

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4826

European-Finnish (FIN) AF: 0.0297 AC: 316 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0307 AC: 2091 AN: 68034

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0285 Hom.: 218

Bravo AF: 0.0213

TwinsUK AF: 0.0367 AC: 136

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0340 AC: 292

ExAC AF: 0.0249 AC: 3026

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 17, 2025

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria.

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary xanthinuria type 1 Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Xanthinuria type II Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.012
DANN	Benign	0.28
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N
PhyloP100		-2.8
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.0080
Sift	Benign	0.53	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.033
ClinPred		0.00049	T
GERP RS		-9.7
Varity_R		0.070
gMVP		0.39
Mutation Taster		=82/18	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: rs17323225; hg19: chr2-31593265; COSMIC: COSV65149455;