20-46034991-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020708.5(SLC12A5):c.96C>T(p.Thr32Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,968 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 20 hom. )

Consequence

SLC12A5
NM_020708.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -8.14

Publications

1 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: 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, 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 20-46034991-C-T is Benign according to our data. Variant chr20-46034991-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00208 (316/152154) while in subpopulation NFE AF = 0.00363 (247/67982). AF 95% confidence interval is 0.00326. There are 3 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.96C>T	p.Thr32Thr	synonymous_variant	Exon 2 of 26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2 link	c.165C>T	p.Thr55Thr	synonymous_variant	Exon 2 of 26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.96C>T	p.Thr32Thr	synonymous_variant	Exon 2 of 26	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

316

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.00251

AC:

630

AN:

251462

AF XY:

0.00261

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00363

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00328

AC:

4798

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2328

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000783

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00312

AC:

269

AN:

86256

European-Finnish (FIN)

AF:

0.00197

AC:

105

AN:

53416

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00376

AC:

4176

AN:

1111960

Other (OTH)

AF:

0.00255

AC:

154

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

279

557

836

1114

1393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00208

AC:

316

AN:

152154

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41512

American (AMR)

AF:

0.000523

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00228

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00363

AC:

247

AN:

67982

Other (OTH)

AF:

0.000951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.00188

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC12A5: BP4, BP7, BS2 -

May 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 34

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.56

(source)

DANN

Benign

0.64

PhyloP100

-8.1

Mutation Taster

=289/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over