4-9920506-C-T

Variant names:

• chr4-9920506-C-T
• rs3733591
• NM_020041.3:c.881G>A

Variant summary

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

The NM_020041.3(SLC2A9):​c.881G>A​(p.Arg294His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,614,018 control chromosomes in the GnomAD database, including 43,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R294R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3490 hom., cov: 33)
  • Exomes 𝑓: 0.21 (40307 hom.)
• Consequence: SLC2A9 NM_020041.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0290
• Publications: 90 publications found

Genes affected

SLC2A9 (HGNC:13446): (solute carrier family 2 member 9) This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SLC2A9 Gene-Disease associations (from GenCC):

• hypouricemia, renal, 2

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary renal hypouricemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=7.065905E-6).
• BP6: Variant 4-9920506-C-T is Benign according to our data. Variant chr4-9920506-C-T is described in ClinVar as Benign. ClinVar VariationId is 350213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A9	NM_020041.3	c.881G>A	p.Arg294His	missense_variant	Exon 7 of 12	ENST00000264784.8	NP_064425.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A9	ENST00000264784.8	c.881G>A	p.Arg294His	missense_variant	Exon 7 of 12	1	NM_020041.3	ENSP00000264784.3
SLC2A9	ENST00000309065.7	c.794G>A	p.Arg265His	missense_variant	Exon 8 of 13	1		ENSP00000311383.3
SLC2A9	ENST00000505104.5	n.915G>A		non_coding_transcript_exon_variant	Exon 8 of 12	1
SLC2A9	ENST00000506583.5	c.794G>A	p.Arg265His	missense_variant	Exon 9 of 14	5		ENSP00000422209.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27517 AN: 152118 Hom.: 3490 Cov.: 33

Gnomad AFR AF: 0.0689

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.246 AC: 61854 AN: 251088 AF XY: 0.252

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.671

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.214 AC: 313476 AN: 1461782 Hom.: 40307 Cov.: 38 AF XY: 0.219 AC XY: 159222 AN XY: 727190

African (AFR) AF: 0.0624 AC: 2090 AN: 33480

American (AMR) AF: 0.223 AC: 9958 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 4239 AN: 26136

East Asian (EAS) AF: 0.691 AC: 27447 AN: 39698

South Asian (SAS) AF: 0.361 AC: 31132 AN: 86256

European-Finnish (FIN) AF: 0.240 AC: 12802 AN: 53356

Middle Eastern (MID) AF: 0.176 AC: 1017 AN: 5768

European-Non Finnish (NFE) AF: 0.190 AC: 211802 AN: 1111974

Other (OTH) AF: 0.215 AC: 12989 AN: 60394

GnomAD4 genome AF: 0.181 AC: 27522 AN: 152236 Hom.: 3490 Cov.: 33 AF XY: 0.190 AC XY: 14133 AN XY: 74442

African (AFR) AF: 0.0688 AC: 2860 AN: 41558

American (AMR) AF: 0.194 AC: 2961 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 508 AN: 3466

East Asian (EAS) AF: 0.662 AC: 3420 AN: 5166

South Asian (SAS) AF: 0.380 AC: 1834 AN: 4828

European-Finnish (FIN) AF: 0.243 AC: 2582 AN: 10606

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12794 AN: 68006

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.194 Hom.: 16777

Bravo AF: 0.171

TwinsUK AF: 0.201 AC: 746

ALSPAC AF: 0.186 AC: 717

ESP6500AA AF: 0.0713 AC: 314

ESP6500EA AF: 0.189 AC: 1629

ExAC AF: 0.245 AC: 29794

Asia WGS AF: 0.454 AC: 1573 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.182

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19723617, 21658257) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Hypouricemia, renal, 2 Benign:1

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T;.;T
MetaRNN	Benign	0.0000071	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		-0.029
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.094
MPC		0.14
ClinPred		0.022	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.43
Mutation Taster		=98/2	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: rs3733591; hg19: chr4-9922130; COSMIC: COSV53319201; COSMIC: COSV53319201;