NM_000340.2:c.1432C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000340.2(SLC2A2):c.1432C>G(p.Leu478Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,612 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L478L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 7 hom. )

Consequence

SLC2A2
NM_000340.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.127

Publications

13 publications found

Variant links:

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

SLC2A2 links:

ENSG00000286856 (HGNC:):

ENSG00000286856 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010517448).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000907 (138/152188) while in subpopulation SAS AF = 0.00249 (12/4824). AF 95% confidence interval is 0.00144. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000340.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC2A2	NM_000340.2	MANE Select	c.1432C>G	p.Leu478Val	missense	Exon 11 of 11	NP_000331.1
SLC2A2	NM_001278658.2		c.1075C>G	p.Leu359Val	missense	Exon 10 of 10	NP_001265587.1
SLC2A2	NM_001278659.2		c.913C>G	p.Leu305Val	missense	Exon 10 of 10	NP_001265588.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC2A2	ENST00000314251.8	TSL:1 MANE Select	c.1432C>G	p.Leu478Val	missense	Exon 11 of 11	ENSP00000323568.3
SLC2A2	ENST00000497642.5	TSL:1	n.*899C>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000418456.1
SLC2A2	ENST00000497642.5	TSL:1	n.*899C>G		3_prime_UTR	Exon 10 of 10	ENSP00000418456.1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00106

AC:

266

AN:

250256

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.000986

GnomAD4 exome

AF:

0.00130

AC:

1894

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

966

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33454

American (AMR)

AF:

0.000135

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00220

AC:

190

AN:

86254

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00139

AC:

1549

AN:

1111806

Other (OTH)

AF:

0.00133

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000907

AC:

138

AN:

152188

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41554

American (AMR)

AF:

0.000393

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00144

AC:

AN:

67984

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000759

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00103

AC:

125

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi-Bickel syndrome (2)

Type 2 diabetes mellitus;C3495427:Fanconi-Bickel syndrome (2)

not provided (1)

SLC2A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.6

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.24

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.81

M_CAP

Benign

0.0089

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.49

PhyloP100

0.13

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.28

REVEL

Benign

0.090

Sift

Benign

0.36

Sift4G

Benign

0.74

Polyphen

0.043

Vest4

0.075

MVP

0.52

MPC

0.17

ClinPred

0.0043

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.068

gMVP

0.48

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over