Variant 20-46049668-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_020708.5(SLC12A5):c.2059G>A(p.Val687Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,606,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

SLC12A5
NM_020708.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.96

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.29500952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A5	NM_020708.5 linkuse as main transcript	c.2059G>A	p.Val687Met	missense_variant	17/26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2 linkuse as main transcript	c.2128G>A	p.Val710Met	missense_variant	17/26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 linkuse as main transcript	c.2059G>A	p.Val687Met	missense_variant	17/26	1	NM_020708.5	ENSP00000243964	A1	Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000825

AC:

AN:

1454218

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

722498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

T;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.33

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.72

P;P

Vest4

0.26

MutPred

0.35

Gain of catalytic residue at V710 (P = 0.1007);.;

MVP

0.56

MPC

1.5

ClinPred

0.91

GERP RS

4.3

Varity_R

0.23

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over