chr1-42943311-CCCGTCAGCTT-C

Variant names:

• chr1-42943311-CCCGTCAGCTT-C
• rs587784393
• NM_006516.4:c.19_28delAAGCTGACGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006516.4(SLC2A1):​c.19_28delAAGCTGACGG​(p.Lys7ValfsTer30) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC2A1 NM_006516.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.56
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 312 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-42943311-CCCGTCAGCTT-C is Pathogenic according to our data. Variant chr1-42943311-CCCGTCAGCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 159924.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A1	NM_006516.4	MANE Select	c.19_28delAAGCTGACGG	p.Lys7ValfsTer30	frameshift splice_region	Exon 2 of 10	NP_006507.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A1	ENST00000426263.10	TSL:1 MANE Select	c.19_28delAAGCTGACGG	p.Lys7ValfsTer30	frameshift splice_region	Exon 2 of 10	ENSP00000416293.2
	SLC2A1	ENST00000958848.1		c.19_28delAAGCTGACGG	p.Lys7ValfsTer30	frameshift splice_region	Exon 2 of 10	ENSP00000628907.1
	SLC2A1	ENST00000938862.1		c.19_28delAAGCTGACGG	p.Lys7ValfsTer30	frameshift splice_region	Exon 2 of 10	ENSP00000608921.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Encephalopathy due to GLUT1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587784393; hg19: chr1-43408982;