Genetic Variant SLC12A1:p.Arg116His (chr15-48208066-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_000338.3(SLC12A1):c.347G>A(p.Arg116His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,613,608 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 30 hom. )

Consequence

SLC12A1
NM_000338.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:6

Conservation

PhyloP100: 10.0

Publications

16 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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.02112645).

BP6

Variant 15-48208066-G-A is Benign according to our data. Variant chr15-48208066-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445491.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00324 (494/152254) while in subpopulation AMR AF = 0.00576 (88/15290). AF 95% confidence interval is 0.00478. There are 0 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 30 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.347G>A	p.Arg116His	missense	Exon 2 of 27	NP_000329.2	Q13621-1
SLC12A1	NM_001184832.2		c.347G>A	p.Arg116His	missense	Exon 2 of 27	NP_001171761.1	Q13621-3
SLC12A1	NM_001384136.1		c.347G>A	p.Arg116His	missense	Exon 2 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.347G>A	p.Arg116His	missense	Exon 2 of 27	ENSP00000370381.3	Q13621-1
SLC12A1	ENST00000330289.10	TSL:1	c.347G>A	p.Arg116His	missense	Exon 1 of 9	ENSP00000331550.6	Q8IUN5
SLC12A1	ENST00000646012.1		c.347G>A	p.Arg116His	missense	Exon 2 of 28	ENSP00000495813.1	A0A2R8Y6V7

Frequencies

GnomAD3 genomes

AF:

0.00325

AC:

494

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00467

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00346

AC:

861

AN:

248770

AF XY:

0.00351

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.00469

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00514

Gnomad OTH exome

AF:

0.00492

GnomAD4 exome

AF:

0.00457

AC:

6680

AN:

1461354

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

3219

AN XY:

726902

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00501

AC:

224

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00483

AC:

126

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00206

AC:

110

AN:

53380

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00536

AC:

5954

AN:

1111662

Other (OTH)

AF:

0.00379

AC:

229

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

360

720

1080

1440

1800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.00324

AC:

494

AN:

152254

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41554

American (AMR)

AF:

0.00576

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00467

AC:

318

AN:

68024

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

120

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:

0.00465

Hom.:

Bravo

AF:

0.00398

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00334

AC:

405

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00498

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Bartter disease type 1 (3)

not specified (2)

SLC12A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.021

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.6

PhyloP100

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.85

Sift

Benign

0.044

Sift4G

Uncertain

0.045

Polyphen

0.99

Vest4

0.84

MVP

0.95

MPC

0.70

ClinPred

0.047

GERP RS

5.6

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.25

gMVP

0.81

Mutation Taster

=11/89

disease causing (ClinVar)

(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