rs78388808

Positions:

• chr1-42929683-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_006516.4(SLC2A1):​c.777C>T​(p.Ile259=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,808 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: SLC2A1 NM_006516.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.622

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-42929683-G-A is Benign according to our data. Variant chr1-42929683-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=2}. Variant chr1-42929683-G-A is described in Lovd as [Likely_benign]. Variant chr1-42929683-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.622 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.777C>T	p.Ile259=	synonymous_variant	6/10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.777C>T	p.Ile259=	synonymous_variant	6/10	1	NM_006516.4	ENSP00000416293	P1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000713 AC: 179 AN: 251084 Hom.: 0 AF XY: 0.000752 AC XY: 102 AN XY: 135706

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0000937

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00120 AC: 1752 AN: 1461508 Hom.: 3 Cov.: 33 AF XY: 0.00120 AC XY: 869 AN XY: 727056

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74476

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000614 Hom.: 0

Bravo AF: 0.000722

EpiCase AF: 0.000981

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC2A1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Encephalopathy due to GLUT1 deficiency Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2014	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 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. -

Dystonia 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2017

This alteration is classified as likely 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. -

GLUT1 deficiency syndrome 1, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.88

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: rs78388808; hg19: chr1-43395354;