NM_020708.5:c.2143T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020708.5(SLC12A5):c.2143T>C(p.Phe715Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC12A5
NM_020708.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.02

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 34
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
epilepsy of infancy with migrating focal seizures
Inheritance: AR Classification: STRONG Submitted by: G2P
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, idiopathic generalized, susceptibility to, 14
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, PanelApp Australia, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC12A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2913103).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020708.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_020708.5	MANE Select	c.2143T>C	p.Phe715Leu	missense	Exon 17 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.2212T>C	p.Phe738Leu	missense	Exon 17 of 26	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.2143T>C	p.Phe715Leu	missense	Exon 17 of 26	ENSP00000243964.4	Q9H2X9-2
SLC12A5	ENST00000616202.4	TSL:1	c.613-8729T>C		intron	N/A	ENSP00000478369.1	M4PM71
SLC12A5	ENST00000626937.2	TSL:1	c.510-9847T>C		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719734

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

42500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25708

East Asian (EAS)

AF:

0.00

AC:

AN:

39350

South Asian (SAS)

AF:

0.00

AC:

AN:

83362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107256

Other (OTH)

AF:

0.0000166

AC:

AN:

60082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 34 (1)

Epilepsy, idiopathic generalized, susceptibility to, 14;C4225257:Developmental and epileptic encephalopathy, 34 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Benign

-0.063

Eigen_PC

Benign

0.098

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.29

MetaSVM

Uncertain

0.093

MutationAssessor

Benign

1.5

PhyloP100

8.0

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.44

Sift

Benign

0.039

Sift4G

Benign

0.17

Polyphen

0.012

Vest4

0.45

MutPred

0.42

Gain of disorder (P = 0.0818)

MVP

0.75

MPC

1.3

ClinPred

0.98

GERP RS

4.4

Varity_R

0.63

gMVP

0.69

Mutation Taster

=74/26

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over