rs587776600

Variant names:

• chr20-46726907-AG-A
• rs587776600
• NM_030777.4:c.1334delG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_030777.4(SLC2A10):​c.1334delG​(p.Gly445GlufsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002048382: Functional analyses of patient cells demonstrate a lack of protein in homozygous patients and about half of wild type expression in heterozygotes (Coucke 2006)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SLC2A10 NM_030777.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.48
• Publications: 7 publications found

Genes affected

SLC2A10 (HGNC:13444): (solute carrier family 2 member 10) This gene encodes a member of the class III facilitative glucose transporter family. The encoded protein plays a role in regulation of glucose homeostasis. Mutations in this gene have been associated with arterial tortuosity syndrome.[provided by RefSeq, Dec 2009]

SLC2A10 Gene-Disease associations (from GenCC):

• arterial tortuosity syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002048382: Functional analyses of patient cells demonstrate a lack of protein in homozygous patients and about half of wild type expression in heterozygotes (Coucke 2006).; SCV004222787: The most pronounced variant effect results in severely reduced mRNA and protein expression in homozygous patient cells compared to unaffected controls. PMID: 16550171, 34847858; SCV004847427: "In vitro functional studies using of patient cells demonstrate a lack of protein in homozygous patients and about half of wild type expression in heterozygotes (Coucke 2006 PMID: 16550171), suggesting that this variant affects protein function."; SCV000250733: Published functional studies demonstrate a damaging effect in SLC2A10-encoded protein levels in individuals homozygous for the variant that showed nearly absent expression, while heterozygous carriers in the family expressed about half the amount of protein compared to wild-type and deficiencies in protein transport (Coucke et al., 2006; Nemeth et al., 2016)
• PP5: Variant 20-46726907-AG-A is Pathogenic according to our data. Variant chr20-46726907-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030777.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A10	NM_030777.4	MANE Select	c.1334delG	p.Gly445GlufsTer40	frameshift	Exon 3 of 5	NP_110404.1	O95528

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A10	ENST00000359271.4	TSL:1 MANE Select	c.1334delG	p.Gly445GlufsTer40	frameshift	Exon 3 of 5	ENSP00000352216.2	O95528
	SLC2A10	ENST00000862794.1		c.1628delG	p.Gly543GlufsTer40	frameshift	Exon 3 of 5	ENSP00000532853.1
	SLC2A10	ENST00000862792.1		c.1315delG	p.Glu439LysfsTer26	frameshift	Exon 3 of 6	ENSP00000532851.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251486 AF XY: 0.000103

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 259 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125 AN XY: 727242

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000219 AC: 244 AN: 1112010

Other (OTH) AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74344

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Arterial tortuosity syndrome (10)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	not provided (1)
1	-	-	SLC2A10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=28/172	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776600; hg19: chr20-45355546;