1-42929964-C-T

Position:

• chr1-42929964-C-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.588G>A​(p.Pro196=) 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 (★★).

• 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

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=-0.57).
• BP6: Variant 1-42929964-C-T is Benign according to our data. Variant chr1-42929964-C-T is described in ClinVar as [Benign]. Clinvar id is 95414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42929964-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.588G>A	p.Pro196=	synonymous_variant	5/10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.588G>A	p.Pro196=	synonymous_variant	5/10	1	NM_006516.4	ENSP00000416293	P1

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

GnomAD3 exomes AF: 0.184 AC: 46362 AN: 251344 Hom.: 4683 AF XY: 0.189 AC XY: 25702 AN XY: 135830

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 SAS exome AF: 0.188

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

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.0803

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.184

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

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.0754

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.183

Alfa AF: 0.175 Hom.: 1927

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Encephalopathy due to GLUT1 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

Dystonia 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.57
CADD	Benign	7.2
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229682; hg19: chr1-43395635; COSMIC: COSV65286860; COSMIC: COSV65286860;