chr2-31367919-C-G

Variant names:

• chr2-31367919-C-G
• rs761926
• NM_000379.4:c.2197+42G>C

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.2197+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,596,796 control chromosomes in the GnomAD database, including 71,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5434 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66380 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.152
• Publications: 16 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=-0.81).
• BP6: Variant 2-31367919-C-G is Benign according to our data. Variant chr2-31367919-C-G is described in ClinVar as Benign. ClinVar VariationId is 1239092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.2197+42G>C		intron_variant	Intron 20 of 35	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.2194+42G>C		intron_variant	Intron 20 of 35		XP_011531397.1
XDH	XM_011533096.3	c.2197+42G>C		intron_variant	Intron 20 of 28		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.2197+42G>C		intron_variant	Intron 20 of 35	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37642 AN: 151958 Hom.: 5435 Cov.: 32

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.308 AC: 77411 AN: 251396 AF XY: 0.309

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.357

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.299 AC: 432177 AN: 1444720 Hom.: 66380 Cov.: 27 AF XY: 0.301 AC XY: 216861 AN XY: 719958

African (AFR) AF: 0.0777 AC: 2574 AN: 33136

American (AMR) AF: 0.393 AC: 17555 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6317 AN: 26016

East Asian (EAS) AF: 0.364 AC: 14424 AN: 39586

South Asian (SAS) AF: 0.352 AC: 30258 AN: 85918

European-Finnish (FIN) AF: 0.302 AC: 16106 AN: 53376

Middle Eastern (MID) AF: 0.232 AC: 1334 AN: 5744

European-Non Finnish (NFE) AF: 0.298 AC: 326858 AN: 1096418

Other (OTH) AF: 0.280 AC: 16751 AN: 59826

GnomAD4 genome AF: 0.247 AC: 37635 AN: 152076 Hom.: 5434 Cov.: 32 AF XY: 0.253 AC XY: 18802 AN XY: 74348

African (AFR) AF: 0.0890 AC: 3694 AN: 41516

American (AMR) AF: 0.320 AC: 4893 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3468

East Asian (EAS) AF: 0.355 AC: 1830 AN: 5154

South Asian (SAS) AF: 0.362 AC: 1746 AN: 4820

European-Finnish (FIN) AF: 0.320 AC: 3381 AN: 10570

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

European-Non Finnish (NFE) AF: 0.300 AC: 20376 AN: 67950

Other (OTH) AF: 0.250 AC: 529 AN: 2114

Alfa AF: 0.271 Hom.: 1217

Bravo AF: 0.240

Asia WGS AF: 0.369 AC: 1281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.7
DANN	Benign	0.56
PhyloP100		0.15
Mutation Taster		=100/0	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: rs761926; hg19: chr2-31590785; COSMIC: COSV65147626;