20-46056217-G-A

Position:

• chr20-46056217-G-A

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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]

SLC12A5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC12A5. . Gene score misZ 4.7022 (greater than the threshold 3.09). Trascript score misZ 6.2616 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 34, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, epilepsy, idiopathic generalized, susceptibility to, 14.
• 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: {Uncertain_significance=1, Benign=3}. 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. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.2855G>A	p.Arg952His	missense_variant	22/26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.2924G>A	p.Arg975His	missense_variant	22/26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2855G>A	p.Arg952His	missense_variant	22/26	1	NM_020708.5	ENSP00000243964.4

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

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. -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

SLC12A5: BP4, BS1, BS2 -

SLC12A5-related disorder Benign:1

Likely benign, no assertion criteria provided

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). -

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;.
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;