rs61742739

Variant names:

• chr16-31490477-A-G
• rs61742739
• NM_003041.4:c.1961A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 6.19

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• 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	c.1961A>G	p.Asn654Ser	missense_variant	Exon 14 of 14	ENST00000330498.4	NP_003032.1
RUSF1	NM_022744.4	c.*358T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000327237.7	NP_073581.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152180 Hom.: 7 Cov.: 33

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

GnomAD3 exomes AF: 0.00560 AC: 1391 AN: 248370 Hom.: 9 AF XY: 0.00559 AC XY: 752 AN XY: 134486

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 SAS 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.: 58 Cov.: 31 AF XY: 0.00693 AC XY: 5042 AN XY: 727104

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.0306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00815

Gnomad4 OTH exome AF: 0.00715

GnomAD4 genome AF: 0.00514 AC: 783 AN: 152298 Hom.: 7 Cov.: 33 AF XY: 0.00494 AC XY: 368 AN XY: 74482

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00765

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00879 Hom.: 9

Bravo AF: 0.00584

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00523 AC: 635

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00836

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial renal glucosuria Pathogenic:1 Uncertain:2 Benign:1

Feb 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

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. -

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. -

not provided Uncertain:1 Benign: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	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.67
Sift	Benign	0.050	D
Sift4G	Uncertain	0.031	D
Polyphen		0.88	P
Vest4		0.27
MVP		0.98
MPC		0.49
ClinPred		0.079	T
GERP RS		5.3
Varity_R		0.28
gMVP		0.72

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: rs61742739; hg19: chr16-31501798;