17-7284228-G-C

Variant names:

• chr17-7284228-G-C
• NM_001042.3:c.576G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001042.3(SLC2A4):​c.576G>C​(p.Leu192Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,612 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC2A4 NM_001042.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

Genes affected

SLC2A4 (HGNC:11009): (solute carrier family 2 member 4) This gene is a member of the solute carrier family 2 (facilitated glucose transporter) family and encodes a protein that functions as an insulin-regulated facilitative glucose transporter. In the absence of insulin, this integral membrane protein is sequestered within the cells of muscle and adipose tissue. Within minutes of insulin stimulation, the protein moves to the cell surface and begins to transport glucose across the cell membrane. Mutations in this gene have been associated with noninsulin-dependent diabetes mellitus (NIDDM). [provided by RefSeq, Jul 2008]

ENSG00000263342 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A4	NM_001042.3	c.576G>C	p.Leu192Phe	missense_variant	Exon 6 of 11	ENST00000317370.13	NP_001033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A4	ENST00000317370.13	c.576G>C	p.Leu192Phe	missense_variant	Exon 6 of 11	1	NM_001042.3	ENSP00000320935.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460612 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726646

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.576G>C (p.L192F) alteration is located in exon 6 (coding exon 6) of the SLC2A4 gene. This alteration results from a G to C substitution at nucleotide position 576, causing the leucine (L) at amino acid position 192 to be replaced by a phenylalanine (F). 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	-0.15	T
PhyloP100		2.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;.;D
Sift4G	Benign	0.093	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.71
MutPred		0.64		Gain of catalytic residue at L192 (P = 0.1902);Gain of catalytic residue at L192 (P = 0.1902);.;
MVP		0.84
MPC		0.49
ClinPred		0.99	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.52
Mutation Taster		=58/42	polymorphism

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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Other links and lift over

hg19: chr17-7187547;