NM_020708.5:c.355C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_020708.5(SLC12A5):c.355C>A(p.Arg119Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,082 control chromosomes in the GnomAD database, including 1,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R119R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.029 ( 173 hom., cov: 32)

Exomes 𝑓: 0.027 ( 1016 hom. )

Consequence

SLC12A5
NM_020708.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.61

Publications

10 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 20-46035852-C-A is Benign according to our data. Variant chr20-46035852-C-A is described in ClinVar as [Benign]. Clinvar id is 475656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.355C>A	p.Arg119Arg	synonymous_variant	Exon 4 of 26	ENST00000243964.7	NP_065759.1	Q9H2X9-2
SLC12A5	NM_001134771.2 link	c.424C>A	p.Arg142Arg	synonymous_variant	Exon 4 of 26		NP_001128243.1	Q9H2X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.355C>A	p.Arg119Arg	synonymous_variant	Exon 4 of 26	1	NM_020708.5	ENSP00000243964.4		Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4428

AN:

152238

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00799

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.0539

Gnomad EAS

AF:

0.0283

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0414

AC:

10390

AN:

251198

AF XY:

0.0373

show subpopulations

Gnomad AFR exome

AF:

0.00572

Gnomad AMR exome

AF:

0.150

Gnomad ASJ exome

AF:

0.0513

Gnomad EAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0390

GnomAD4 exome

AF:

0.0275

AC:

40179

AN:

1461728

Hom.:

1016

Cov.:

AF XY:

0.0272

AC XY:

19774

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00517

AC:

173

AN:

33480

American (AMR)

AF:

0.150

AC:

6691

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0529

AC:

1381

AN:

26120

East Asian (EAS)

AF:

0.0354

AC:

1404

AN:

39696

South Asian (SAS)

AF:

0.0299

AC:

2578

AN:

86244

European-Finnish (FIN)

AF:

0.0193

AC:

1033

AN:

53412

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0225

AC:

25038

AN:

1111938

Other (OTH)

AF:

0.0298

AC:

1797

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2217

4434

6651

8868

11085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0291

AC:

4433

AN:

152354

Hom.:

173

Cov.:

AF XY:

0.0309

AC XY:

2301

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00796

AC:

331

AN:

41572

American (AMR)

AF:

0.118

AC:

1810

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0539

AC:

187

AN:

3468

East Asian (EAS)

AF:

0.0281

AC:

146

AN:

5190

South Asian (SAS)

AF:

0.0273

AC:

132

AN:

4830

European-Finnish (FIN)

AF:

0.0184

AC:

196

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1520

AN:

68036

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

213

427

640

854

1067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0251

Hom.:

109

Bravo

AF:

0.0349

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0231

EpiControl

AF:

0.0244

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

Developmental and epileptic encephalopathy, 34

Benign:1

Feb 04, 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

-0.24

CADD

Benign

9.7

(source)

DANN

Benign

0.65

PhyloP100

1.6

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_020708.5:c.355C>A

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