rs76362149

Positions:

• chr3-170999148-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000340.2(SLC2A2):​c.1087G>T​(p.Ala363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,610,670 control chromosomes in the GnomAD database, including 2 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 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: SLC2A2 NM_000340.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.09

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031058013).
• BP6: Variant 3-170999148-C-A is Benign according to our data. Variant chr3-170999148-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199012.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr3-170999148-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (165/152166) while in subpopulation NFE AF= 0.00159 (108/67990). AF 95% confidence interval is 0.00135. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC2A2	NM_000340.2	c.1087G>T	p.Ala363Ser	missense_variant	9/11	ENST00000314251.8	NP_000331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC2A2	ENST00000314251.8	c.1087G>T	p.Ala363Ser	missense_variant	9/11	1	NM_000340.2	ENSP00000323568	P1
SLC2A2	ENST00000497642.5	c.*554G>T		3_prime_UTR_variant, NMD_transcript_variant	8/10	1		ENSP00000418456
	ENST00000655926.1	n.291+4123C>A		intron_variant, non_coding_transcript_variant
SLC2A2	ENST00000469787.1	c.*554G>T		3_prime_UTR_variant, NMD_transcript_variant	8/10	2		ENSP00000417918

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 165 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 250756 Hom.: 0 AF XY: 0.00147 AC XY: 199 AN XY: 135506

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00160 AC: 2327 AN: 1458504 Hom.: 2 Cov.: 29 AF XY: 0.00156 AC XY: 1131 AN XY: 725744

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74382

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.000756

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00161 AC: 196

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi-Bickel syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Reported as a heterozygous SNP in an individual with myelomeningocele (Ruggiero et al., 2015); This variant is associated with the following publications: (PMID: 30950137, 25776730) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2015	- -

SLC2A2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.083	T
Polyphen		0.49	P
Vest4		0.55
MVP		0.85
MPC		0.43
ClinPred		0.073	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs76362149; hg19: chr3-170716937;