chr20-46045891-G-A

Position:

• chr20-46045891-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_020708.5(SLC12A5):​c.1583G>A​(p.Gly528Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A5 NM_020708.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.08

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 20-46045891-G-A is Pathogenic according to our data. Variant chr20-46045891-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.1583G>A	p.Gly528Asp	missense_variant	13/26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.1652G>A	p.Gly551Asp	missense_variant	13/26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.1583G>A	p.Gly528Asp	missense_variant	13/26	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	PMID:27436767;26333769 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2021	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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SLC12A5 function (PMID: 26333769). ClinVar contains an entry for this variant (Variation ID: 217905). This variant is also known as G551D. This missense change has been observed in individual(s) with SLC12A5-related conditions (PMID: 26333769). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 528 of the SLC12A5 protein (p.Gly528Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.12	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.93	P;P
Vest4		0.76
MutPred		0.57		Gain of sheet (P = 0.0827);.;
MVP		0.92
MPC		2.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.97

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: rs863225305; hg19: chr20-44674530;