3-170998041-G-A

Variant names:

• chr3-170998041-G-A
• rs5398
• NM_000340.2:c.1437C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000340.2(SLC2A2):​c.1437C>T​(p.Phe479Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,122 control chromosomes in the GnomAD database, including 78,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.38 (12175 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65875 hom.)
• Consequence: SLC2A2 NM_000340.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.739

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]

ENSG00000286856 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-170998041-G-A is Benign according to our data. Variant chr3-170998041-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130348.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}. Variant chr3-170998041-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.739 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A2	NM_000340.2	c.1437C>T	p.Phe479Phe	synonymous_variant	Exon 11 of 11	ENST00000314251.8	NP_000331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A2	ENST00000314251.8	c.1437C>T	p.Phe479Phe	synonymous_variant	Exon 11 of 11	1	NM_000340.2	ENSP00000323568.3

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56935 AN: 151836 Hom.: 12148 Cov.: 32

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.307 AC: 76887 AN: 250066 Hom.: 12705 AF XY: 0.304 AC XY: 41164 AN XY: 135376

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.282

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.295 AC: 431072 AN: 1461168 Hom.: 65875 Cov.: 37 AF XY: 0.293 AC XY: 213184 AN XY: 726908

Gnomad4 AFR exome AF: 0.605

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.318

GnomAD4 genome AF: 0.375 AC: 57005 AN: 151954 Hom.: 12175 Cov.: 32 AF XY: 0.371 AC XY: 27569 AN XY: 74260

Gnomad4 AFR AF: 0.595

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.364

Alfa AF: 0.308 Hom.: 17610

Bravo AF: 0.392

Asia WGS AF: 0.290 AC: 1012 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.298

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

-

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. -

Dec 04, 2015

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Phe479Phe in exon 11 of SLC2A2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 63.54% (840/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs5398). -

Fanconi-Bickel syndrome Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Type 2 diabetes mellitus Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Associated with neonatal diabetes, glycogen accumulation in liver leading to hepatomegaly. -

not provided Benign:1

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.0
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5398; hg19: chr3-170715830; COSMIC: COSV58587971; COSMIC: COSV58587971;