9-127400003-G-C

Variant names:

• chr9-127400003-G-C
• NM_014580.5:c.523G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014580.5(SLC2A8):​c.523G>C​(p.Ala175Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC2A8 NM_014580.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A8	NM_014580.5	c.523G>C	p.Ala175Pro	missense_variant	Exon 4 of 10	ENST00000373371.8	NP_055395.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A8	ENST00000373371.8	c.523G>C	p.Ala175Pro	missense_variant	Exon 4 of 10	1	NM_014580.5	ENSP00000362469.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460792 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>C (p.A175P) alteration is located in exon 4 (coding exon 4) of the SLC2A8 gene. This alteration results from a G to C substitution at nucleotide position 523, causing the alanine (A) at amino acid position 175 to be replaced by a proline (P). 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;D;D;.;T;.;.;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.022	.;D;D;D;D;D;T;T
Sift4G	Uncertain	0.040	D;T;T;T;T;T;T;T
Polyphen		1.0	.;D;.;.;D;.;.;.
Vest4		0.92
MutPred		0.70		.;Loss of catalytic residue at A175 (P = 0.0077);.;.;Loss of catalytic residue at A175 (P = 0.0077);.;.;.;
MVP		0.94
MPC		0.85
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.76
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130162282;