11-26673416-T-C

Variant names:

• chr11-26673416-T-C
• rs758740051
• NM_178498.4:c.1693A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178498.4(SLC5A12):​c.1693A>G​(p.Ser565Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,448,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: SLC5A12 NM_178498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.473

Genes affected

SLC5A12 (HGNC:28750): (solute carrier family 5 member 12) Normal blood lactate is maintained at about 1.5 mM, and little filtered lactate is excreted in urine. Reabsorption of lactate is mediated by the low-affinity Na(+)-coupled lactate transporter SLC5A12 in the initial part of the proximal tubule and by the high-affinity Na(+)-coupled lactate transporter SLC5A8 (MIM 608044) in the distal proximal tubule (Gopal et al., 2007 [PubMed 17692818]).[supplied by OMIM, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022324055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A12	NM_178498.4	c.1693A>G	p.Ser565Gly	missense_variant	Exon 14 of 15	ENST00000396005.8	NP_848593.2
SLC5A12	XM_006718155.4	c.1360A>G	p.Ser454Gly	missense_variant	Exon 14 of 15		XP_006718218.1
SLC5A12	XM_011519920.3	c.1129A>G	p.Ser377Gly	missense_variant	Exon 15 of 16		XP_011518222.1
SLC5A12	XM_017017244.2	c.1129A>G	p.Ser377Gly	missense_variant	Exon 15 of 16		XP_016872733.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A12	ENST00000396005.8	c.1693A>G	p.Ser565Gly	missense_variant	Exon 14 of 15	1	NM_178498.4	ENSP00000379326.3
SLC5A12	ENST00000527405.5	n.*299A>G		non_coding_transcript_exon_variant	Exon 14 of 15	2		ENSP00000436011.1
SLC5A12	ENST00000527405.5	n.*299A>G		3_prime_UTR_variant	Exon 14 of 15	2		ENSP00000436011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000294 AC: 7 AN: 237706 Hom.: 0 AF XY: 0.0000232 AC XY: 3 AN XY: 129068

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 SAS exome AF: 0.000248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000967 AC: 14 AN: 1448434 Hom.: 0 Cov.: 29 AF XY: 0.00000972 AC XY: 7 AN XY: 720180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1693A>G (p.S565G) alteration is located in exon 14 (coding exon 14) of the SLC5A12 gene. This alteration results from a A to G substitution at nucleotide position 1693, causing the serine (S) at amino acid position 565 to be replaced by a glycine (G). 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	Benign	0.058
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.9
DANN	Benign	0.84
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.20	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.20
Sift	Benign	0.47	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.21		Loss of glycosylation at S565 (P = 0.0175);
MVP		0.32
MPC		0.17
ClinPred		0.015	T
GERP RS		-2.9
Varity_R		0.036
gMVP		0.15

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: rs758740051; hg19: chr11-26694963;