rs79849424

chr20-46726190-C-Gchr20-46726190-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030777.4(SLC2A10):c.1154C>G(p.Ala385Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,230 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A385V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (93 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (228 hom.)
• Consequence: SLC2A10 NM_030777.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0200

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024423003).
• BP6: Variant 20-46726190-C-G is Benign according to our data. Variant chr20-46726190-C-G is described in ClinVar as [Benign]. Clinvar id is 139174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46726190-C-G is described in Lovd as [Benign]. Variant chr20-46726190-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A10	NM_030777.4	c.1154C>G	p.Ala385Gly	missense_variant	2/5	ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4	c.1154C>G	p.Ala385Gly	missense_variant	2/5	1	NM_030777.4	P1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2824 AN: 152276 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00575

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0114 AC: 2858 AN: 251270 Hom.: 81 AF XY: 0.0125 AC XY: 1695 AN XY: 135872

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0542

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00588 AC: 8594 AN: 1461836 Hom.: 228 Cov.: 33 AF XY: 0.00706 AC XY: 5135 AN XY: 727226

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0509

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00798

GnomAD4 genome AF: 0.0186 AC: 2833 AN: 152394 Hom.: 93 Cov.: 33 AF XY: 0.0188 AC XY: 1400 AN XY: 74526

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.00568

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0561

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00571 Hom.: 5

Bravo AF: 0.0195

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0495 AC: 218

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0134 AC: 1626

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arterial tortuosity syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: SLC2A10 c.1154C>G (p.Ala385Gly) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 251270 control chromosomes in the gnomAD database, including 81 homozygotes. The observed variant frequency is approximately 7.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC2A10 causing Aortopathy phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1154C>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported at our laboratory (FBN1 c.349C>T, p.Q117*), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 02, 2015	This alteration is classified as 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	1.3
Dann	Benign	0.69
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.11
Sift	Benign	0.41	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.065
ClinPred		0.00097	T
GERP RS		-1.7
Varity_R		0.027
gMVP		0.36

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: rs79849424; hg19: chr20-45354829;