NM_014580.5:c.379C>T

Variant names:

• chr9-127398064-C-T
• rs1405503520
• NM_014580.5:c.379C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014580.5(SLC2A8):​c.379C>T​(p.Arg127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,436,672 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: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SLC2A8 NM_014580.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70
• Publications: 1 publications found

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

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, 0.984

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A8	NM_014580.5	MANE Select	c.379C>T	p.Arg127Cys	missense	Exon 3 of 10	NP_055395.2
	SLC2A8	NM_001271711.2		c.379C>T	p.Arg127Cys	missense	Exon 3 of 9	NP_001258640.1	Q5VVV9
	SLC2A8	NM_001271712.2		c.-64+778C>T		intron	N/A	NP_001258641.1	A0A087WT42

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A8	ENST00000373371.8	TSL:1 MANE Select	c.379C>T	p.Arg127Cys	missense	Exon 3 of 10	ENSP00000362469.3	Q9NY64
	SLC2A8	ENST00000373360.7	TSL:1	c.379C>T	p.Arg127Cys	missense	Exon 3 of 9	ENSP00000362458.3	Q5VVV9
	SLC2A8	ENST00000954537.1		c.379C>T	p.Arg127Cys	missense	Exon 3 of 10	ENSP00000624596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000947 AC: 2 AN: 211208 AF XY: 0.0000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.0000181 AC: 26 AN: 1436672 Hom.: 0 Cov.: 31 AF XY: 0.0000224 AC XY: 16 AN XY: 713956

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.0000231 AC: 1 AN: 43210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 38846

South Asian (SAS) AF: 0.00 AC: 0 AN: 84012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.0000226 AC: 25 AN: 1105658

Other (OTH) AF: 0.00 AC: 0 AN: 59604

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		2.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.87		Loss of methylation at R127 (P = 0.0077)
MVP		0.98
MPC		0.90
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.0049	Neutral
Varity_R		0.88
gMVP		0.89
Mutation Taster		=60/40	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

Other links and lift over

dbSNP: rs1405503520; hg19: chr9-130160343;