rs863225306

chr20-46041337-T-A

Variant summary

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

The NM_020708.5(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 NM_020708.5 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 where missense usually causes diseases, SLC12A5
• 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	UniProt
SLC12A5	NM_020708.5	c.863T>A	p.Leu288His	missense_variant	8/26	ENST00000243964.7
SLC12A5	NM_001134771.2	c.932T>A	p.Leu311His	missense_variant	8/26

Ensembl

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