16-31484874-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003041.4(SLC5A2):​c.254C>A​(p.Ala85Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC5A2
NM_003041.4 missense

Scores

15
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC5A2NM_003041.4 linkuse as main transcriptc.254C>A p.Ala85Glu missense_variant 3/14 ENST00000330498.4
SLC5A2XM_006721072.5 linkuse as main transcriptc.254C>A p.Ala85Glu missense_variant 3/13
SLC5A2XM_024450402.2 linkuse as main transcriptc.254C>A p.Ala85Glu missense_variant 3/11
SLC5A2NR_130783.2 linkuse as main transcriptn.268C>A non_coding_transcript_exon_variant 3/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC5A2ENST00000330498.4 linkuse as main transcriptc.254C>A p.Ala85Glu missense_variant 3/141 NM_003041.4 P1P31639-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251146
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461758
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 22, 2023The c.254C>A (p.A85E) alteration is located in exon 3 (coding exon 3) of the SLC5A2 gene. This alteration results from a C to A substitution at nucleotide position 254, causing the alanine (A) at amino acid position 85 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.0
.;H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.96
MutPred
0.89
.;Gain of disorder (P = 0.0251);
MVP
0.98
MPC
0.88
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.99
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755812371; hg19: chr16-31496195; API