rs145210664

chr3-171014682-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_000340.2(SLC2A2):c.158G>A(p.Arg53Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (1 hom.)
• Consequence: SLC2A2 NM_000340.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.957

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014140785).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000723 (110/152242) while in subpopulation AMR AF= 0.00163 (25/15296). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A2	NM_000340.2	c.158G>A	p.Arg53Gln	missense_variant	3/11	ENST00000314251.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A2	ENST00000314251.8	c.158G>A	p.Arg53Gln	missense_variant	3/11	1	NM_000340.2	P1
	ENST00000655926.1	n.291+19657C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000680 AC: 171 AN: 251376 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000787 AC: 1151 AN: 1461610 Hom.: 1 Cov.: 32 AF XY: 0.000754 AC XY: 548 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.000933

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000723 AC: 110 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74434

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000793 Hom.: 0

Bravo AF: 0.000831

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2018	The R53Q variant in the SLC2A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R53Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R53Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R53Q as a variant of uncertain significance. -

Fanconi-Bickel syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 26, 2021

- -

Type 2 diabetes mellitus;C3495427:Fanconi-Bickel syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	0.63	D;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.28	B
Vest4		0.16
MVP		0.58
MPC		0.17
ClinPred		0.014	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs145210664; hg19: chr3-170732471; COSMIC: COSV58584288;