chr2-31366981-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 30 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 -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 VariationId is 255967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.2211C>T	p.Ile737Ile	synonymous	Exon 21 of 36	NP_000370.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.2211C>T	p.Ile737Ile	synonymous	Exon 21 of 36	ENSP00000368727.3
	XDH	ENST00000879520.1		c.2319C>T	p.Ile773Ile	synonymous	Exon 21 of 36	ENSP00000549579.1
	XDH	ENST00000879524.1		c.2220C>T	p.Ile740Ile	synonymous	Exon 21 of 36	ENSP00000549583.1

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

GnomAD2 exomes AF: 0.309 AC: 77569 AN: 251432 AF XY: 0.310

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 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

African (AFR) AF: 0.0755 AC: 2526 AN: 33478

American (AMR) AF: 0.388 AC: 17363 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6340 AN: 26134

East Asian (EAS) AF: 0.352 AC: 13990 AN: 39700

South Asian (SAS) AF: 0.347 AC: 29963 AN: 86256

European-Finnish (FIN) AF: 0.304 AC: 16255 AN: 53414

Middle Eastern (MID) AF: 0.232 AC: 1340 AN: 5768

European-Non Finnish (NFE) AF: 0.306 AC: 339848 AN: 1111938

Other (OTH) AF: 0.282 AC: 17050 AN: 60390

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

African (AFR) AF: 0.0878 AC: 3649 AN: 41572

American (AMR) AF: 0.320 AC: 4889 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1782 AN: 5168

South Asian (SAS) AF: 0.354 AC: 1706 AN: 4822

European-Finnish (FIN) AF: 0.321 AC: 3400 AN: 10586

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20859 AN: 68010

Other (OTH) AF: 0.250 AC: 529 AN: 2116

Alfa AF: 0.287 Hom.: 29844

Bravo AF: 0.242

Asia WGS AF: 0.360 AC: 1251 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.297

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary xanthinuria type 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Xanthinuria type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.015
DANN	Benign	0.63
PhyloP100		-0.29
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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