Genetic Variant NM_014580.5:c.283G>C (chr9-127397968-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014580.5(SLC2A8):c.283G>C(p.Gly95Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SLC2A8
NM_014580.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.51

Publications

0 publications found

Variant links:

Genes affected

SLC2A8 (HGNC:13812): (solute carrier family 2 member 8) This gene belongs to the solute carrier 2A family, which includes intracellular glucose transporters. Based on sequence comparison, the glucose transporters are grouped into three classes and this gene is a member of class II. The encoded protein, like other members of the family, contains several conserved residues and motifs and 12 transmembrane domains with both amino and carboxyl ends being on the cytosolic side of the membrane. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]

SLC2A8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014580.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC2A8	NM_014580.5	MANE Select	c.283G>C	p.Gly95Arg	missense	Exon 3 of 10	NP_055395.2
SLC2A8	NM_001271711.2		c.283G>C	p.Gly95Arg	missense	Exon 3 of 9	NP_001258640.1	Q5VVV9
SLC2A8	NM_001271712.2		c.-64+682G>C		intron	N/A	NP_001258641.1	A0A087WT42

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC2A8	ENST00000373371.8	TSL:1 MANE Select	c.283G>C	p.Gly95Arg	missense	Exon 3 of 10	ENSP00000362469.3	Q9NY64
SLC2A8	ENST00000373360.7	TSL:1	c.283G>C	p.Gly95Arg	missense	Exon 3 of 9	ENSP00000362458.3	Q5VVV9
SLC2A8	ENST00000954537.1		c.283G>C	p.Gly95Arg	missense	Exon 3 of 10	ENSP00000624596.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1384714

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683798

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31580

American (AMR)

AF:

0.00

AC:

AN:

36000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25142

East Asian (EAS)

AF:

0.00

AC:

AN:

35820

South Asian (SAS)

AF:

0.00

AC:

AN:

79364

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4786

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079814

Other (OTH)

AF:

0.00

AC:

AN:

57838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

PhyloP100

9.5

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.96

Gain of MoRF binding (P = 0.0221)

MVP

0.99

MPC

0.84

ClinPred

1.0

GERP RS

5.5

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.91

gMVP

0.94

Mutation Taster

=23/77

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over