2-31388501-T-C

Variant names:

• chr2-31388501-T-C
• rs206847
• NM_000379.4:c.496-206A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000379.4(XDH):​c.496-206A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 152,066 control chromosomes in the GnomAD database, including 34,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.66 (34229 hom., cov: 32)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.779
• Publications: 4 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 (BayesDel_noAF=-0.84).
• BP6: Variant 2-31388501-T-C is Benign according to our data. Variant chr2-31388501-T-C is described in ClinVar as Benign. ClinVar VariationId is 1282207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.496-206A>G		intron_variant	Intron 6 of 35	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.496-206A>G		intron_variant	Intron 6 of 35		XP_011531397.1
XDH	XM_011533096.3	c.496-206A>G		intron_variant	Intron 6 of 28		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.496-206A>G		intron_variant	Intron 6 of 35	1	NM_000379.4	ENSP00000368727.3
XDH	ENST00000491727.5	n.39-206A>G		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101012 AN: 151948 Hom.: 34193 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.664

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.665 AC: 101104 AN: 152066 Hom.: 34229 Cov.: 32 AF XY: 0.659 AC XY: 48987 AN XY: 74330

African (AFR) AF: 0.764 AC: 31709 AN: 41488

American (AMR) AF: 0.612 AC: 9365 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2491 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1862 AN: 5146

South Asian (SAS) AF: 0.551 AC: 2647 AN: 4806

European-Finnish (FIN) AF: 0.620 AC: 6552 AN: 10572

Middle Eastern (MID) AF: 0.712 AC: 208 AN: 292

European-Non Finnish (NFE) AF: 0.651 AC: 44238 AN: 67978

Other (OTH) AF: 0.662 AC: 1400 AN: 2114

Alfa AF: 0.652 Hom.: 77743

Bravo AF: 0.670

Asia WGS AF: 0.463 AC: 1613 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.2
DANN	Benign	0.39
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs206847; hg19: chr2-31611367;