rs896545456

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000338.3(SLC12A1):c.769G>A(p.Gly257Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,594,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G257D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SLC12A1
NM_000338.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.60

Publications

2 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:

LOC128966560 (HGNC:):

LOC128966560 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 15-48229233-G-A is Pathogenic according to our data. Variant chr15-48229233-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 548675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.769G>A	p.Gly257Ser	missense	Exon 6 of 27	NP_000329.2	Q13621-1
SLC12A1	NM_001184832.2		c.769G>A	p.Gly257Ser	missense	Exon 6 of 27	NP_001171761.1	Q13621-3
SLC12A1	NM_001384136.1		c.769G>A	p.Gly257Ser	missense	Exon 6 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.769G>A	p.Gly257Ser	missense	Exon 6 of 27	ENSP00000370381.3	Q13621-1
SLC12A1	ENST00000330289.10	TSL:1	c.769G>A	p.Gly257Ser	missense	Exon 5 of 9	ENSP00000331550.6	Q8IUN5
SLC12A1	ENST00000558252.5	TSL:1	n.4892G>A		non_coding_transcript_exon	Exon 2 of 23

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1441970

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

714952

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33266

American (AMR)

AF:

0.00

AC:

AN:

41344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25750

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39150

South Asian (SAS)

AF:

0.00

AC:

AN:

82854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000254

AC:

AN:

1101652

Other (OTH)

AF:

0.0000167

AC:

AN:

59788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bartter disease type 1 (1)

Nephrocalcinosis;C0392525:Nephrolithiasis (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.4

PhyloP100

9.6

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.060

Polyphen

1.0

Vest4

0.99

MutPred

0.95

Gain of glycosylation at G257 (P = 0.0065)

MVP

0.99

MPC

0.63

ClinPred

1.0

GERP RS

5.8

Varity_R

0.92

gMVP

0.94

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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