rs1553785033

Variant names:

• chr3-170998321-C-T
• rs1553785033
• NM_000340.2:c.1246G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000340.2(SLC2A2):​c.1246G>A​(p.Gly416Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC2A2 NM_000340.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

SLC2A2 (HGNC:11006): (solute carrier family 2 member 2) This gene encodes an integral plasma membrane glycoprotein of the liver, islet beta cells, intestine, and kidney epithelium. The encoded protein mediates facilitated bidirectional glucose transport. Because of its low affinity for glucose, it has been suggested as a glucose sensor. Mutations in this gene are associated with susceptibility to diseases, including Fanconi-Bickel syndrome and noninsulin-dependent diabetes mellitus (NIDDM). Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

SLC2A2 Gene-Disease associations (from GenCC):

• glycogen storage disease due to GLUT2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P
• neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ENSG00000286856 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000340.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 3-170998321-C-T is Pathogenic according to our data. Variant chr3-170998321-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 445147.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A2	NM_000340.2	c.1246G>A	p.Gly416Ser	missense_variant	Exon 10 of 11	ENST00000314251.8	NP_000331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A2	ENST00000314251.8	c.1246G>A	p.Gly416Ser	missense_variant	Exon 10 of 11	1	NM_000340.2	ENSP00000323568.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi-Bickel syndrome Pathogenic:1

Feb 01, 2016

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variation is found to be likely pathogenic on the basis on in silico tools: Mutationtaster (http://www.mutationtaster.org/), http://sift.jcvi.org/, http://genetics.bwh.harvard.edu/pph2/ Mother and father were found to be carrier of this variation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.87		Loss of catalytic residue at G416 (P = 0.0325);
MVP		0.93
MPC		0.63
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.81
gMVP		0.91
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1553785033; hg19: chr3-170716110;