NM_006516.4:c.588G>A

Variant names:

• chr1-42929964-C-T
• rs2229682
• NM_006516.4:c.588G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006516.4(SLC2A1):​c.588G>A​(p.Pro196Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,880 control chromosomes in the GnomAD database, including 31,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P196P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2279 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29389 hom.)
• Consequence: SLC2A1 NM_006516.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -5.43
• Publications: 23 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-42929964-C-T is Benign according to our data. Variant chr1-42929964-C-T is described in ClinVar as Benign. ClinVar VariationId is 95414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.588G>A	p.Pro196Pro	synonymous_variant	Exon 5 of 10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.588G>A	p.Pro196Pro	synonymous_variant	Exon 5 of 10	1	NM_006516.4	ENSP00000416293.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23827 AN: 151950 Hom.: 2275 Cov.: 32

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.0754

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.184 AC: 46362 AN: 251344 AF XY: 0.189

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.0761

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.197 AC: 288354 AN: 1461812 Hom.: 29389 Cov.: 35 AF XY: 0.198 AC XY: 144029 AN XY: 727210

African (AFR) AF: 0.0382 AC: 1278 AN: 33480

American (AMR) AF: 0.203 AC: 9068 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4632 AN: 26134

East Asian (EAS) AF: 0.0803 AC: 3187 AN: 39700

South Asian (SAS) AF: 0.188 AC: 16236 AN: 86256

European-Finnish (FIN) AF: 0.225 AC: 11994 AN: 53416

Middle Eastern (MID) AF: 0.182 AC: 1050 AN: 5766

European-Non Finnish (NFE) AF: 0.207 AC: 229774 AN: 1111944

Other (OTH) AF: 0.184 AC: 11135 AN: 60392

GnomAD4 genome AF: 0.157 AC: 23837 AN: 152068 Hom.: 2279 Cov.: 32 AF XY: 0.159 AC XY: 11816 AN XY: 74318

African (AFR) AF: 0.0458 AC: 1901 AN: 41508

American (AMR) AF: 0.214 AC: 3271 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 628 AN: 3464

East Asian (EAS) AF: 0.0754 AC: 390 AN: 5172

South Asian (SAS) AF: 0.174 AC: 840 AN: 4816

European-Finnish (FIN) AF: 0.228 AC: 2415 AN: 10572

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.204 AC: 13848 AN: 67956

Other (OTH) AF: 0.183 AC: 386 AN: 2104

Alfa AF: 0.174 Hom.: 2495

Bravo AF: 0.149

Asia WGS AF: 0.117 AC: 407 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.201

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Jun 27, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Encephalopathy due to GLUT1 deficiency Benign:3

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dystonia 9 Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Feb 22, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GLUT1 deficiency syndrome 1, autosomal recessive Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cryohydrocytosis with reduced stomatin Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.2
DANN	Benign	0.88
PhyloP100		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2229682; hg19: chr1-43395635; COSMIC: COSV65286860; COSMIC: COSV65286860;