rs890647462

Variant names:

• chr20-46049752-T-C
• rs890647462
• NM_020708.5:c.2143T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020708.5(SLC12A5):​c.2143T>C​(p.Phe715Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.02

Genes affected

SLC12A5 (HGNC:13818): (solute carrier family 12 member 5) K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2913103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.2143T>C	p.Phe715Leu	missense_variant	Exon 17 of 26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.2212T>C	p.Phe738Leu	missense_variant	Exon 17 of 26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2143T>C	p.Phe715Leu	missense_variant	Exon 17 of 26	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450288 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 719734

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2212T>C (p.F738L) alteration is located in exon 17 (coding exon 17) of the SLC12A5 gene. This alteration results from a T to C substitution at nucleotide position 2212, causing the phenylalanine (F) at amino acid position 738 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epilepsy, idiopathic generalized, susceptibility to, 14;C4225257:Developmental and epileptic encephalopathy, 34 Uncertain:1

Dec 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 34 Uncertain:1

Mar 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 715 of the SLC12A5 protein (p.Phe715Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC12A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 574875). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC12A5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	-0.063
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.039	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.012	B;B
Vest4		0.45
MutPred		0.42		Gain of disorder (P = 0.0818);.;
MVP		0.75
MPC		1.3
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.63
gMVP		0.69

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: rs890647462; hg19: chr20-44678391;