rs11537641

Positions:

• chr1-42930743-G-A
• chr1-42930743-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006516.4(SLC2A1):​c.399C>T​(p.Cys133=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,609,076 control chromosomes in the GnomAD database, including 30,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2440 hom., cov: 32)
  • Exomes 𝑓: 0.20 (28559 hom.)
• Consequence: SLC2A1 NM_006516.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -1.50

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-42930743-G-A is Benign according to our data. Variant chr1-42930743-G-A is described in ClinVar as [Benign]. Clinvar id is 95411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42930743-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A1	NM_006516.4	c.399C>T	p.Cys133=	synonymous_variant	4/10	ENST00000426263.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A1	ENST00000426263.10	c.399C>T	p.Cys133=	synonymous_variant	4/10	1	NM_006516.4	P1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25905 AN: 152052 Hom.: 2436 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0991

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.190 AC: 46816 AN: 246772 Hom.: 4677 AF XY: 0.194 AC XY: 25969 AN XY: 133848

Gnomad AFR exome AF: 0.0925

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.0999

Gnomad SAS exome AF: 0.198

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.196 AC: 285607 AN: 1456906 Hom.: 28559 Cov.: 34 AF XY: 0.197 AC XY: 142748 AN XY: 725080

Gnomad4 AFR exome AF: 0.0901

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.0917

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.170 AC: 25920 AN: 152170 Hom.: 2440 Cov.: 32 AF XY: 0.173 AC XY: 12844 AN XY: 74388

Gnomad4 AFR AF: 0.0939

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.0991

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.187

Alfa AF: 0.191 Hom.: 1328

Bravo AF: 0.164

Asia WGS AF: 0.141 AC: 492 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.198

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dystonia 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Encephalopathy due to GLUT1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 08, 2016	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2016

This alteration is classified as 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. -

Childhood onset GLUT1 deficiency syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

GLUT1 deficiency syndrome 1, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cryohydrocytosis with reduced stomatin Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Epilepsy, idiopathic generalized, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.6
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs11537641; hg19: chr1-43396414; COSMIC: COSV65287469; COSMIC: COSV65287469;