Genetic Variant SLC2A8:p.Asp66Tyr (chr9-127397515-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014580.5(SLC2A8):c.196G>T(p.Asp66Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,429,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SLC2A8
NM_014580.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.559

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A8	NM_014580.5 link	c.196G>T	p.Asp66Tyr	missense_variant	Exon 2 of 10	ENST00000373371.8	NP_055395.2	Q9NY64Q8WZ05A0A024R871

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A8	ENST00000373371.8 link	c.196G>T	p.Asp66Tyr	missense_variant	Exon 2 of 10	1	NM_014580.5	ENSP00000362469.3		Q9NY64

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1277490

Hom.:

Cov.:

AF XY:

0.00000956

AC XY:

AN XY:

627464

show subpopulations

Gnomad4 AFR exome

AF:

0.000522

Gnomad4 AMR exome

AF:

0.0000603

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.66e-7

Gnomad4 OTH exome

AF:

0.0000189

GnomAD4 genome

AF:

0.000263

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>T (p.D66Y) alteration is located in exon 2 (coding exon 2) of the SLC2A8 gene. This alteration results from a G to T substitution at nucleotide position 196, causing the aspartic acid (D) at amino acid position 66 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.26

T;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.030

D;D;D

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.92

P;.;D

Vest4

0.34

MutPred

0.54

Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);

MVP

0.86

MPC

0.73

ClinPred

0.90

GERP RS

4.5

Varity_R

0.12

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over