NM_030777.4:c.243C>G

Variant names:

• chr20-46725279-C-G
• rs80358230
• NM_030777.4:c.243C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PP3_Strong PP5_Very_Strong BS1_Supporting BS2_Supporting

The NM_030777.4(SLC2A10):​c.243C>G​(p.Ser81Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,830 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (2 hom.)
• Consequence: SLC2A10 NM_030777.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 3.13
• Publications: 26 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 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 20-46725279-C-G is Pathogenic according to our data. Variant chr20-46725279-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000109 (16/1461830) while in subpopulation MID AF = 0.00278 (16/5754). AF 95% confidence interval is 0.00174. There are 2 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.243C>G	p.Ser81Arg	missense	Exon 2 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.243C>G	p.Ser81Arg	missense	Exon 2 of 5	ENSP00000352216.2	O95528
	SLC2A10	ENST00000862794.1		c.537C>G	p.Ser179Arg	missense	Exon 2 of 5	ENSP00000532853.1
	SLC2A10	ENST00000862792.1		c.243C>G	p.Ser81Arg	missense	Exon 2 of 6	ENSP00000532851.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461830 Hom.: 2 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Arterial tortuosity syndrome (8)
1	-	-	not provided (1)
1	-	-	SLC2A10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Gain of methylation at S81 (P = 0.0157)
MVP		0.97
MPC		0.36
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.91
Mutation Taster		=11/89	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: rs80358230; hg19: chr20-45353918;