1-42927113-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_006516.4(SLC2A1):ā€‹c.1407G>Cā€‹(p.Gln469His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q469Q) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

SLC2A1
NM_006516.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
SLC2A1 (HGNC:11005): (solute carrier family 2 member 1) This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. Mutations in this gene have been found in a family with paroxysmal exertion-induced dyskinesia. [provided by RefSeq, Apr 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_006516.4
PP2
Missense variant in the SLC2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.9256 (below the threshold of 3.09). Trascript score misZ: 4.6729 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, dystonia 9, epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, myoclonic-astatic epilepsy, childhood onset GLUT1 deficiency syndrome 2, hereditary cryohydrocytosis with reduced stomatin, encephalopathy due to GLUT1 deficiency.
BP4
Computational evidence support a benign effect (MetaRNN=0.12191799).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC2A1NM_006516.4 linkc.1407G>C p.Gln469His missense_variant 10/10 ENST00000426263.10 NP_006507.2 P11166Q59GX2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC2A1ENST00000426263.10 linkc.1407G>C p.Gln469His missense_variant 10/101 NM_006516.4 ENSP00000416293.2 P11166

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251080
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135754
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152334
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 12 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Uncertain significance. -
Dystonia 9 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Encephalopathy due to GLUT1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Childhood onset GLUT1 deficiency syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
GLUT1 deficiency syndrome 1, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 28, 2024This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 469 of the SLC2A1 protein (p.Gln469His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 374095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC2A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 07, 2019Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Hereditary cryohydrocytosis with reduced stomatin Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Myopathy;C0149931:Migraine;C0151786:Muscle weakness;C0231528:Myalgia;C1850830:Exercise-induced myalgia;C1968729:Increased muscle glycogen content;C4021745:Abnormality of the musculature Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaMay 05, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.37
T
Eigen
Benign
-0.13
Eigen_PC
Benign
0.079
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
0.74
N
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.19
Sift
Benign
0.28
T
Sift4G
Benign
0.19
T
Polyphen
0.0
B
Vest4
0.21
MutPred
0.19
Gain of catalytic residue at Q469 (P = 0.0974);
MVP
0.64
MPC
0.84
ClinPred
0.23
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.059
gMVP
0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201748668; hg19: chr1-43392784; API