rs1060502313

Variant names:

• chr20-46725101-T-G
• rs1060502313
• NM_030777.4:c.65T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_030777.4(SLC2A10):​c.65T>G​(p.Phe22Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC2A10 NM_030777.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A10	NM_030777.4	MANE Select	c.65T>G	p.Phe22Cys	missense	Exon 2 of 5	NP_110404.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A10	ENST00000359271.4	TSL:1 MANE Select	c.65T>G	p.Phe22Cys	missense	Exon 2 of 5	ENSP00000352216.2
	SLC2A10	ENST00000611837.1	TSL:2	n.217T>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arterial tortuosity syndrome Uncertain:1

Oct 01, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine with cysteine at codon 22 of the SLC2A10 protein (p.Phe22Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SLC2A10-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.79		Loss of stability (P = 0.1603)
MVP		0.95
MPC		0.47
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.70
gMVP		0.67
Mutation Taster		=29/71	disease causing

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: rs1060502313; hg19: chr20-45353740;