dbSNP rs17428448: SLC12A1:c.2154+86T>G (chr15-48259397-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000338.3(SLC12A1):c.2154+86T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 932,660 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0049 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0056 ( 22 hom. )

Consequence

SLC12A1
NM_000338.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.298

Publications

1 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):

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

SLC12A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00486 (739/152208) while in subpopulation NFE AF = 0.00718 (488/68012). AF 95% confidence interval is 0.00665. There are 1 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3 link	c.2154+86T>G	intron_variant	Intron 17 of 26	ENST00000380993.8	NP_000329.2	Q13621-1Q8IUN5
SLC12A1	NM_001184832.2 link	c.2154+86T>G	intron_variant	Intron 17 of 26		NP_001171761.1	Q13621-3B4DPF4
SLC12A1	NM_001384136.1 link	c.2154+86T>G	intron_variant	Intron 17 of 26		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8 link	c.2154+86T>G		intron_variant	Intron 17 of 26	5	NM_000338.3	ENSP00000370381.3		Q13621-1

Frequencies

GnomAD3 genomes

AF:

0.00485

AC:

738

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00387

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00717

Gnomad OTH

AF:

0.00527

GnomAD4 exome

AF:

0.00555

AC:

4332

AN:

780452

Hom.:

AF XY:

0.00529

AC XY:

2191

AN XY:

414554

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

20354

American (AMR)

AF:

0.00295

AC:

128

AN:

43458

Ashkenazi Jewish (ASJ)

AF:

0.000413

AC:

AN:

21814

East Asian (EAS)

AF:

0.00

AC:

AN:

36634

South Asian (SAS)

AF:

0.000193

AC:

AN:

72372

European-Finnish (FIN)

AF:

0.00979

AC:

511

AN:

52192

Middle Eastern (MID)

AF:

0.000689

AC:

AN:

4352

European-Non Finnish (NFE)

AF:

0.00699

AC:

3437

AN:

491390

Other (OTH)

AF:

0.00531

AC:

201

AN:

37886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

221

442

663

884

1105

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:

0.00486

AC:

739

AN:

152208

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

368

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41520

American (AMR)

AF:

0.00386

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0117

AC:

124

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00718

AC:

488

AN:

68012

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

139

174

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:

0.00374

Hom.:

Bravo

AF:

0.00408

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.96

(source)

DANN

Benign

0.83

PhyloP100

0.30

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over