rs1385129

Positions:

• chr1-42943295-G-A
• chr1-42943295-G-C

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.45C>T​(p.Ala15=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,611,710 control chromosomes in the GnomAD database, including 41,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3828 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37408 hom.)
• Consequence: SLC2A1 NM_006516.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -1.83

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=-0.51).
• BP6: Variant 1-42943295-G-A is Benign according to our data. Variant chr1-42943295-G-A is described in ClinVar as [Benign]. Clinvar id is 95413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42943295-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.45C>T	p.Ala15=	synonymous_variant	2/10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.45C>T	p.Ala15=	synonymous_variant	2/10	1	NM_006516.4	ENSP00000416293	P1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33325 AN: 151980 Hom.: 3829 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.242 AC: 60244 AN: 249400 Hom.: 7435 AF XY: 0.242 AC XY: 32720 AN XY: 135056

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.288

Gnomad SAS exome AF: 0.268

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.224 AC: 327183 AN: 1459610 Hom.: 37408 Cov.: 32 AF XY: 0.225 AC XY: 163661 AN XY: 726156

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.217

Gnomad4 EAS exome AF: 0.254

Gnomad4 SAS exome AF: 0.270

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.219 AC: 33347 AN: 152100 Hom.: 3828 Cov.: 32 AF XY: 0.224 AC XY: 16659 AN XY: 74358

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.274

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.225

Alfa AF: 0.214 Hom.: 4824

Bravo AF: 0.218

Asia WGS AF: 0.296 AC: 1029 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.212

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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 54% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 50. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Encephalopathy due to GLUT1 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Dystonia 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 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

Jul 15, 2021

- -

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

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.2
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)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1385129; hg19: chr1-43408966; COSMIC: COSV65287476; COSMIC: COSV65287476;