3-170998299-A-G

Variant names:

• chr3-170998299-A-G
• rs28928874
• NM_000340.2:c.1268T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000340.2(SLC2A2):​c.1268T>C​(p.Val423Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V423E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC2A2 NM_000340.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.10
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-170998299-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16101.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000340.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A2	NM_000340.2	MANE Select	c.1268T>C	p.Val423Ala	missense	Exon 10 of 11	NP_000331.1
	SLC2A2	NM_001278658.2		c.911T>C	p.Val304Ala	missense	Exon 9 of 10	NP_001265587.1
	SLC2A2	NM_001278659.2		c.749T>C	p.Val250Ala	missense	Exon 9 of 10	NP_001265588.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A2	ENST00000314251.8	TSL:1 MANE Select	c.1268T>C	p.Val423Ala	missense	Exon 10 of 11	ENSP00000323568.3
	SLC2A2	ENST00000497642.5	TSL:1	n.*735T>C		non_coding_transcript_exon	Exon 9 of 10	ENSP00000418456.1
	SLC2A2	ENST00000497642.5	TSL:1	n.*735T>C		3_prime_UTR	Exon 9 of 10	ENSP00000418456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461558 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.097	T
Polyphen		0.88	P
Vest4		0.81
MutPred		0.65		Loss of glycosylation at S428 (P = 0.0127)
MVP		0.92
MPC		0.60
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.81
gMVP		0.74
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28928874; hg19: chr3-170716088;