16-31484914-C-G

Variant names:

• chr16-31484914-C-G
• rs398122802
• NM_003041.4:c.294C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM2 PP3

The NM_003041.4(SLC5A2):​c.294C>G​(p.Phe98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC5A2 NM_003041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• familial renal glucosuria

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_003041.4 (SLC5A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A2	NM_003041.4	c.294C>G	p.Phe98Leu	missense_variant	Exon 3 of 14	ENST00000330498.4	NP_003032.1
SLC5A2	XM_006721072.5	c.294C>G	p.Phe98Leu	missense_variant	Exon 3 of 13		XP_006721135.3
SLC5A2	XM_024450402.2	c.294C>G	p.Phe98Leu	missense_variant	Exon 3 of 11		XP_024306170.2
SLC5A2	NR_130783.2	n.308C>G		non_coding_transcript_exon_variant	Exon 3 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A2	ENST00000330498.4	c.294C>G	p.Phe98Leu	missense_variant	Exon 3 of 14	1	NM_003041.4	ENSP00000327943.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250580 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.1	.;M
PhyloP100		0.12
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.050	T;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.67		.;Gain of helix (P = 0.2294);
MVP		0.97
MPC		0.91
ClinPred		0.97	D
GERP RS		1.7
Varity_R		0.63
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs398122802; hg19: chr16-31496235;