chr1-42929696-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4BP6BS1

The NM_006516.4(SLC2A1):c.764A>C(p.Lys255Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000309 in 1,613,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K255R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

SLC2A1
NM_006516.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 5.08

Publications

8 publications found

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]

SLC2A1 Gene-Disease associations (from GenCC):

encephalopathy due to GLUT1 deficiency
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
GLUT1 deficiency syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
childhood onset GLUT1 deficiency syndrome 2
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
dystonia 9
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
epilepsy, idiopathic generalized, susceptibility to, 12
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary cryohydrocytosis with reduced stomatin
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

SLC2A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, encephalopathy due to GLUT1 deficiency, dystonia 9, hereditary cryohydrocytosis with reduced stomatin, childhood onset GLUT1 deficiency syndrome 2, childhood absence epilepsy, myoclonic-astatic epilepsy.

BP4

Computational evidence support a benign effect (MetaRNN=0.38487655).

BP6

Variant 1-42929696-T-G is Benign according to our data. Variant chr1-42929696-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159929.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000191 (29/152166) while in subpopulation NFE AF = 0.000397 (27/68016). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4 link	c.764A>C	p.Lys255Thr	missense_variant	Exon 6 of 10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10 link	c.764A>C	p.Lys255Thr	missense_variant	Exon 6 of 10	1	NM_006516.4	ENSP00000416293.2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

251202

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000220

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000322

AC:

470

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000365

AC:

406

AN:

1111992

Other (OTH)

AF:

0.00104

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000191

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Aug 08, 2024

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24215330)

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dystonia 9

Uncertain:1

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Encephalopathy due to GLUT1 deficiency

Uncertain:1

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GLUT1 deficiency syndrome 1, autosomal recessive

Uncertain:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 255 of the SLC2A1 protein (p.Lys255Thr). This variant is present in population databases (rs5811, gnomAD 0.02%). 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: 159929). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt SLC2A1 function with a negative predictive value of 80%. 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 specified

Benign:1

Jun 14, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Mar 21, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

SLC2A1-related disorder

Benign:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Benign

0.042

Eigen_PC

Benign

0.19

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.059

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.5

PhyloP100

5.1

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.4

Sift

Benign

0.11

Sift4G

Benign

0.31

Vest4

0.58

ClinPred

0.10

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.82

Mutation Taster

=26/74

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over