3-171007166-C-T

Variant names:

• chr3-171007166-C-T
• rs5404
• NM_000340.2:c.594G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000340.2(SLC2A2):​c.594G>A​(p.Thr198Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,608,914 control chromosomes in the GnomAD database, including 11,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T198T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2402 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8873 hom.)
• Consequence: SLC2A2 NM_000340.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.14
• Publications: 23 publications found

Genes affected

SLC2A2 (HGNC:11006): (solute carrier family 2 member 2) This gene encodes an integral plasma membrane glycoprotein of the liver, islet beta cells, intestine, and kidney epithelium. The encoded protein mediates facilitated bidirectional glucose transport. Because of its low affinity for glucose, it has been suggested as a glucose sensor. Mutations in this gene are associated with susceptibility to diseases, including Fanconi-Bickel syndrome and noninsulin-dependent diabetes mellitus (NIDDM). Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

SLC2A2 Gene-Disease associations (from GenCC):

• glycogen storage disease due to GLUT2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P
• neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ENSG00000286856 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 3-171007166-C-T is Benign according to our data. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-171007166-C-T is described in CliVar as Benign. Clinvar id is 130351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A2	NM_000340.2	c.594G>A	p.Thr198Thr	synonymous_variant	Exon 5 of 11	ENST00000314251.8	NP_000331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A2	ENST00000314251.8	c.594G>A	p.Thr198Thr	synonymous_variant	Exon 5 of 11	1	NM_000340.2	ENSP00000323568.3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23129 AN: 151730 Hom.: 2397 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.00890

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0930

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.108 AC: 26907 AN: 250208 AF XY: 0.109

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.0675

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.00589

Gnomad FIN exome AF: 0.0926

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.103 AC: 149886 AN: 1457066 Hom.: 8873 Cov.: 30 AF XY: 0.104 AC XY: 75333 AN XY: 725086

African (AFR) AF: 0.295 AC: 9809 AN: 33280

American (AMR) AF: 0.0743 AC: 3310 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3350 AN: 26048

East Asian (EAS) AF: 0.0144 AC: 570 AN: 39646

South Asian (SAS) AF: 0.131 AC: 11295 AN: 86122

European-Finnish (FIN) AF: 0.0964 AC: 5145 AN: 53352

Middle Eastern (MID) AF: 0.139 AC: 802 AN: 5754

European-Non Finnish (NFE) AF: 0.0983 AC: 108912 AN: 1108134

Other (OTH) AF: 0.111 AC: 6693 AN: 60176

GnomAD4 genome AF: 0.152 AC: 23150 AN: 151848 Hom.: 2402 Cov.: 32 AF XY: 0.151 AC XY: 11190 AN XY: 74214

African (AFR) AF: 0.291 AC: 12041 AN: 41378

American (AMR) AF: 0.118 AC: 1800 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3464

East Asian (EAS) AF: 0.00893 AC: 46 AN: 5154

South Asian (SAS) AF: 0.132 AC: 633 AN: 4806

European-Finnish (FIN) AF: 0.0930 AC: 984 AN: 10578

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6807 AN: 67920

Other (OTH) AF: 0.142 AC: 299 AN: 2104

Alfa AF: 0.117 Hom.: 3034

Bravo AF: 0.159

Asia WGS AF: 0.0760 AC: 271 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Fanconi-Bickel syndrome Benign:2

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Type 2 diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

SLC2A2 associated with neonatal diabetes, glycogen accumulation in liver leading to hepatomegaly. rs5404 variant is associated with risk of developing Type II Diabetes Mellitus. However, more studies are required to ascertain the role of rs5404 in neonatal diabetes. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.57
DANN	Benign	0.45
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5404; hg19: chr3-170724955; COSMIC: COSV58589347;