rs780511606

chr20-46035781-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP3 BS1_Supporting

The NM_020708.5(SLC12A5):c.284C>T(p.Pro95Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,611,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC12A5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000092 (14/152196) while in subpopulation NFE AF= 0.000132 (9/68038). AF 95% confidence interval is 0.000068. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.284C>T	p.Pro95Leu	missense_variant	4/26	ENST00000243964.7
SLC12A5	NM_001134771.2	c.353C>T	p.Pro118Leu	missense_variant	4/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.284C>T	p.Pro95Leu	missense_variant	4/26	1	NM_020708.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 41 AN: 249236 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000652

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1459386 Hom.: 0 Cov.: 32 AF XY: 0.000156 AC XY: 113 AN XY: 725726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000600

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.353C>T (p.P118L) alteration is located in exon 4 (coding exon 4) of the SLC12A5 gene. This alteration results from a C to T substitution at nucleotide position 353, causing the proline (P) at amino acid position 118 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 34 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 95 of the SLC12A5 protein (p.Pro95Leu). This variant is present in population databases (rs780511606, gnomAD 0.06%). 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: 377102). 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 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;T;.;T;T;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.2	D;.;.;.;.;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;.;.;.;.;D
Sift4G	Uncertain	0.038	D;D;D;D;D;T;D
Polyphen		0.63	P;.;.;.;.;.;P
Vest4		0.86
MutPred		0.58		Loss of disorder (P = 0.0155);.;.;.;.;.;.;
MVP		0.72
MPC		2.1
ClinPred		0.75	D
GERP RS		4.6
Varity_R		0.63
gMVP		0.91

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: rs780511606; hg19: chr20-44664420;