rs121909741

Variant names:

• chr3-171007171-C-G
• rs121909741
• NM_000340.2:c.589G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-171007171-C-G
• chr3-171007171-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000340.2(SLC2A2):​c.589G>C​(p.Val197Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,412 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V197I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC2A2 NM_000340.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.79
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 3-171007171-C-G is Pathogenic according to our data. Variant chr3-171007171-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1334152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A2	NM_000340.2	c.589G>C	p.Val197Leu	missense_variant	Exon 5 of 11	ENST00000314251.8	NP_000331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A2	ENST00000314251.8	c.589G>C	p.Val197Leu	missense_variant	Exon 5 of 11	1	NM_000340.2	ENSP00000323568.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459412 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726142

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110150

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi-Bickel syndrome Pathogenic:2

Jan 13, 2022

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.66 (>=0.6)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with SLC2A2-related disorder (PMID: 36692815), and a different missense change at the same codon (p.Val197Ile) has been reported to be associated with SLC2A2-related disorder (PMID: 8063045). The variant has been observed in at least two similarly affected unrelated individuals (3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		5.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;.
Vest4		0.84
MutPred		0.86		Loss of catalytic residue at V197 (P = 0.2659);.;
MVP		0.94
MPC		0.62
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.79
Mutation Taster		=28/72	disease causing

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: rs121909741; hg19: chr3-170724960;