1-42927615-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1PM2PP2PP3BP6_Moderate

The NM_006516.4(SLC2A1):c.1268A>G(p.Gln423Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 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 benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q423P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SLC2A1
NM_006516.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.69

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_006516.4

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-42927615-T-C is Benign according to our data. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42927615-T-C is described in CliVar as Likely_benign. Clinvar id is 159923.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4 link	c.1268A>G	p.Gln423Arg	missense_variant	Exon 9 of 10	ENST00000426263.10	NP_006507.2	P11166Q59GX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10 link	c.1268A>G	p.Gln423Arg	missense_variant	Exon 9 of 10	1	NM_006516.4	ENSP00000416293.2		P11166

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 06, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.062

MutationAssessor

Uncertain

2.2

PhyloP100

2.7

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.68

Sift

Benign

0.092

Sift4G

Uncertain

0.047

Polyphen

0.74

Vest4

0.67

MutPred

0.71

Gain of relative solvent accessibility (P = 0.1571);

MVP

0.98

MPC

1.9

ClinPred

0.72

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.89

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.78

Position offset: 0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over