rs863225306

Positions:

• chr20-46041337-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The ENST00000243964.7(SLC12A5):​c.863T>A​(p.Leu288His) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A5 ENST00000243964.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• 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 5 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, 0.838
• PP5: Variant 20-46041337-T-A is Pathogenic according to our data. Variant chr20-46041337-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 217906.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.863T>A	p.Leu288His	missense_variant	8/26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.932T>A	p.Leu311His	missense_variant	8/26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.863T>A	p.Leu288His	missense_variant	8/26	1	NM_020708.5	ENSP00000243964	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	PMID:26333769 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0080	D;.;D
Sift4G	Uncertain	0.037	D;T;D
Polyphen		0.99	D;.;D
Vest4		0.82
MutPred		0.54		Gain of sheet (P = 0.0149);.;.;
MVP		0.43
MPC		2.4
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.98

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: rs863225306; hg19: chr20-44669976;