rs137893258

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000338.3(SLC12A1):c.2255C>T(p.Ala752Val) variant causes a missense change. The variant allele was found at a frequency of 0.00142 in 1,613,410 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A752A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

SLC12A1
NM_000338.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 6.29

Publications

8 publications found

Variant links:

Genes affected

SLC12A1 (HGNC:10910): (solute carrier family 12 member 1) This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

SLC12A1 Gene-Disease associations (from GenCC):

antenatal Bartter syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Bartter disease type 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

SLC12A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021517426).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A1	NM_000338.3	MANE Select	c.2255C>T	p.Ala752Val	missense	Exon 18 of 27	NP_000329.2	Q13621-1
SLC12A1	NM_001184832.2		c.2255C>T	p.Ala752Val	missense	Exon 18 of 27	NP_001171761.1	Q13621-3
SLC12A1	NM_001384136.1		c.2255C>T	p.Ala752Val	missense	Exon 18 of 27	NP_001371065.1	A0A8I5KSK6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A1	ENST00000380993.8	TSL:5 MANE Select	c.2255C>T	p.Ala752Val	missense	Exon 18 of 27	ENSP00000370381.3	Q13621-1
SLC12A1	ENST00000558252.5	TSL:1	n.6378C>T		non_coding_transcript_exon	Exon 14 of 23
SLC12A1	ENST00000560692.5	TSL:1	n.6394C>T		non_coding_transcript_exon	Exon 13 of 22

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00108

AC:

272

AN:

251020

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00147

AC:

2143

AN:

1461260

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1074

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33452

American (AMR)

AF:

0.000246

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00191

AC:

165

AN:

86244

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00164

AC:

1828

AN:

1111546

Other (OTH)

AF:

0.000862

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00103

AC:

156

AN:

152150

Hom.:

Cov.:

AF XY:

0.000874

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41510

American (AMR)

AF:

0.000196

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00125

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00163

AC:

111

AN:

67996

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000835

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bartter disease type 1 (3)

not provided (3)

SLC12A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.15

Eigen

Benign

0.067

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.048

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.4

PhyloP100

6.3

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.020

REVEL

Uncertain

0.41

Sift

Benign

0.45

Sift4G

Benign

0.53

Polyphen

0.22

Vest4

0.87

MVP

0.90

MPC

0.35

ClinPred

0.031

GERP RS

6.0

Varity_R

0.18

gMVP

0.51

Mutation Taster

=59/41

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over