rs142740233

chr20-46056217-G-Achr20-46056217-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_020708.5(SLC12A5):c.2855G>A(p.Arg952His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,188 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (40 hom.)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: 2.97

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC12A5
• BP4: Computational evidence support a benign effect (MetaRNN=0.007701069).
• BP6: Variant 20-46056217-G-A is Benign according to our data. Variant chr20-46056217-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218377.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=1}. Variant chr20-46056217-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00135 (205/152332) while in subpopulation SAS AF= 0.0145 (70/4828). AF 95% confidence interval is 0.0118. There are 2 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A5	NM_020708.5	c.2855G>A	p.Arg952His	missense_variant	22/26	ENST00000243964.7
SLC12A5	NM_001134771.2	c.2924G>A	p.Arg975His	missense_variant	22/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2855G>A	p.Arg952His	missense_variant	22/26	1	NM_020708.5	A1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00335 AC: 842 AN: 251422 Hom.: 13 AF XY: 0.00435 AC XY: 591 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0193

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00216 AC: 3159 AN: 1461856 Hom.: 40 Cov.: 31 AF XY: 0.00279 AC XY: 2029 AN XY: 727236

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00995

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000955

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74486

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00139 Hom.: 1

Bravo AF: 0.000990

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00335 AC: 407

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 14 Uncertain:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -
Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg952His variant, sometimes called p.Arg975His due to a difference in cDNA numbering, in SLC12A5 has been identified in 8 individuals with febrile seizures, segregated with disease in at least 3 affected relatives from 1 family, was present in at least 7 unaffected individuals (PMID: 24668262, 24928908), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg952His variant may slightly impact protein function (PMID: 24668262). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. -

Developmental and epileptic encephalopathy, 34 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

SLC12A5-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

SLC12A5: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.
MutationTaster	Benign	0.64	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.057	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0010	B;B
Vest4		0.73
MVP		0.36
MPC		0.21
ClinPred		0.010	T
GERP RS		3.9
Varity_R		0.071
gMVP		0.70

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: rs142740233; hg19: chr20-44684856;