20-46035854-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020708.5(SLC12A5):c.357G>T(p.Arg119Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 1,614,046 control chromosomes in the GnomAD database, including 4,329 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 0.067 ( 355 hom., cov: 32)

Exomes 𝑓: 0.071 ( 3974 hom. )

Consequence

SLC12A5
NM_020708.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.84

Publications

5 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina
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: Ambry Genetics, PanelApp Australia, Illumina
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC12A5 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_020708.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.51).

BP6

Variant 20-46035854-G-T is Benign according to our data. Variant chr20-46035854-G-T is described in ClinVar as Benign. ClinVar VariationId is 1166970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

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.357G>T	p.Arg119Arg	synonymous	Exon 4 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.426G>T	p.Arg142Arg	synonymous	Exon 4 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.357G>T	p.Arg119Arg	synonymous	Exon 4 of 26	ENSP00000243964.4	Q9H2X9-2
SLC12A5	ENST00000616202.4	TSL:1	c.357G>T	p.Arg119Arg	synonymous	Exon 4 of 7	ENSP00000478369.1	M4PM71
SLC12A5	ENST00000626937.2	TSL:1	c.357G>T	p.Arg119Arg	synonymous	Exon 4 of 7	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes

AF:

0.0667

AC:

10154

AN:

152178

Hom.:

355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0599

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0758

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.0504

Gnomad MID

AF:

0.185

Gnomad NFE

AF:

0.0769

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.0597

AC:

14989

AN:

251202

AF XY:

0.0595

show subpopulations

Gnomad AFR exome

AF:

0.0606

Gnomad AMR exome

AF:

0.0512

Gnomad ASJ exome

AF:

0.0993

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0464

Gnomad NFE exome

AF:

0.0786

Gnomad OTH exome

AF:

0.0916

GnomAD4 exome

AF:

0.0709

AC:

103594

AN:

1461750

Hom.:

3974

Cov.:

AF XY:

0.0698

AC XY:

50758

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0612

AC:

2048

AN:

33480

American (AMR)

AF:

0.0524

AC:

2345

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2632

AN:

26120

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0249

AC:

2151

AN:

86254

European-Finnish (FIN)

AF:

0.0517

AC:

2762

AN:

53400

Middle Eastern (MID)

AF:

0.123

AC:

712

AN:

5766

European-Non Finnish (NFE)

AF:

0.0775

AC:

86150

AN:

1111936

Other (OTH)

AF:

0.0793

AC:

4786

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

5672

11344

17016

22688

28360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3120

6240

9360

12480

15600

<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:

0.0667

AC:

10163

AN:

152296

Hom.:

355

Cov.:

AF XY:

0.0637

AC XY:

4741

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0600

AC:

2494

AN:

41548

American (AMR)

AF:

0.0757

AC:

1159

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

368

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5192

South Asian (SAS)

AF:

0.0191

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0504

AC:

535

AN:

10620

Middle Eastern (MID)

AF:

0.182

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0769

AC:

5230

AN:

68018

Other (OTH)

AF:

0.0995

AC:

210

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

496

993

1489

1986

2482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0761

Hom.:

1059

Bravo

AF:

0.0687

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0876

EpiControl

AF:

0.0888

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 34 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.1

(source)

DANN

Benign

0.61

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over