rs61742739

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003041.4(SLC5A2):c.1961A>G(p.Asn654Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00703 in 1,613,962 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0051 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 58 hom. )

Consequence

SLC5A2
NM_003041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: 6.19

Publications

29 publications found

Variant links:

Genes affected

SLC5A2 (HGNC:11037): (solute carrier family 5 member 2) This gene encodes a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. The encoded protein is the major cotransporter involved in glucose reabsorption in the kidney. Mutations in this gene are associated with renal glucosuria. Two transcript variants, one protein-coding and one not, have been found for this gene. [provided by RefSeq, Feb 2015]

SLC5A2 links:

RUSF1 (HGNC:25848): (RUS family member 1) This gene encodes a putative transmembrane protein containing a conserved DUF647 domain that may be involved in protein-protein interaction. The encoded protein is related to a plant protein that participates in ultraviolet B light-sensing during root morphogenesis. [provided by RefSeq, Feb 2013]

RUSF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010311753).

BP6

Variant 16-31490477-A-G is Benign according to our data. Variant chr16-31490477-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12905.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00514 (783/152298) while in subpopulation NFE AF = 0.00765 (520/68014). AF 95% confidence interval is 0.0071. There are 7 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A2	NM_003041.4 link	c.1961A>G	p.Asn654Ser	missense_variant	Exon 14 of 14	ENST00000330498.4	NP_003032.1	P31639-1
RUSF1	NM_022744.4 link	c.*358T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000327237.7	NP_073581.2	Q96GQ5-1A0A024QZE6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A2	ENST00000330498.4 link	c.1961A>G	p.Asn654Ser	missense_variant	Exon 14 of 14	1	NM_003041.4	ENSP00000327943.3		P31639-1
RUSF1	ENST00000327237.7 link	c.*358T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_022744.4	ENSP00000317579.2		Q96GQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

783

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00764

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00560

AC:

1391

AN:

248370

AF XY:

0.00559

show subpopulations

Gnomad AFR exome

AF:

0.000743

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00824

Gnomad OTH exome

AF:

0.00756

GnomAD4 exome

AF:

0.00722

AC:

10556

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00693

AC XY:

5042

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33476

American (AMR)

AF:

0.00295

AC:

132

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0306

AC:

799

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00815

AC:

9061

AN:

1111964

Other (OTH)

AF:

0.00715

AC:

432

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

660

1319

1979

2638

3298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00514

AC:

783

AN:

152298

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

368

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41560

American (AMR)

AF:

0.00386

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00765

AC:

520

AN:

68014

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00827

Hom.:

Bravo

AF:

0.00584

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.00523

AC:

635

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00769

EpiControl

AF:

0.00836

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial renal glucosuria

Pathogenic:1Uncertain:3Benign:1

Feb 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_003041.3:c.1961A>G in the SLC5A2 gene has an allele frequency of 0.03 in Ashkenazi Jewish subpopulation in the gnomAD database. Although 10 homozygous occurrences are observed in the gnomAD database, renal glucosuria is not lethal in young age. Therefore we did not count this as a strong benign evidence. One individual with renal glucosuria, was a compound heterozygote for this variant and p.Q167fsX186 mutation (PMID: 14614622). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1; PM3. -

Aug 02, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variant was identified, NM_003041.3(SLC5A2):c.1961A>G in exon 14 of 14 of the SLC5A2 gene. This substitution is predicted to create a minor amino acid change from asparagine to serine at position 654 of the protein, NP_003032.1(SLC5A2):p.(Asn654Ser). The asparagine at this position has moderate conservation (100 vertebrates, UCSC), but is located within the SLC5sbd_SGLT2 domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.54% (1489 heterozygotes, 10 homozygotes). The variant has been previously reported pathogenic in patients with renal glucosuria (ClinVar, Calado, J. et al. (2004)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN. -

not provided

Uncertain:1Benign:1

Jan 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple individuals with glucosuria in the literature; the majority of these individuals had a second variant in the SLC5A2 gene, although it is not known whether the variants occurred on the same (in cis) or on opposite alleles (in trans) in some cases (PMID: 37349938, 15110322, 14614622, 18622023, 31672324; Moscoso J et al. (2023) International Journal of Medical Reviews and Case Reports. 7 (6):53-56 https://www.mdpub.net/?mno=152000); Identified as a single heterozygous variant in a patient with chronic kidney disease in the literature, however, additional clinical information was not provided (PMID: 33226606); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 37516996, 18622023, Moscoso[article]2023, 25333069, 31672324, 14569097, 15110322, 30476936, 35982159, 33057194, 14614622, 33226606, 37349938, 37240725) -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC5A2-related disorder

Benign:1

Dec 06, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.4

PhyloP100

6.2

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.67

Sift

Benign

0.050

Sift4G

Uncertain

0.031

Polyphen

0.88

Vest4

0.27

MVP

0.98

MPC

0.49

ClinPred

0.079

GERP RS

5.3

Varity_R

0.28

gMVP

0.72

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over