Genetic Variant SLC12A1:p.Val958Gly (chr15-48288516-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2PM5BP4_Strong

The NM_000338.3(SLC12A1):c.2873T>G(p.Val958Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V958A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

SLC12A1
NM_000338.3 missense, splice_region

Scores

Splicing: ADA: 0.00002974

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.777

Publications

0 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:

ENSG00000309916 (HGNC:):

ENSG00000309916 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-48288516-TG-CGTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3577326.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0648261).

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.2873T>G	p.Val958Gly	missense splice_region	Exon 23 of 27	NP_000329.2	Q13621-1
SLC12A1	NM_001184832.2		c.2873T>G	p.Val958Gly	missense splice_region	Exon 23 of 27	NP_001171761.1	Q13621-3
SLC12A1	NM_001384136.1		c.2873T>G	p.Val958Gly	missense splice_region	Exon 23 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.2873T>G	p.Val958Gly	missense splice_region	Exon 23 of 27	ENSP00000370381.3	Q13621-1
SLC12A1	ENST00000558252.5	TSL:1	n.6996T>G		splice_region non_coding_transcript_exon	Exon 19 of 23
SLC12A1	ENST00000560692.5	TSL:1	n.7012T>G		splice_region non_coding_transcript_exon	Exon 18 of 22

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.14

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.32

M_CAP

Benign

0.056

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-1.3

PhyloP100

0.78

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.11

REVEL

Benign

0.21

Sift

Benign

0.17

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.062

MutPred

0.44

Loss of stability (P = 0.0047)

MVP

0.77

MPC

0.18

ClinPred

0.32

GERP RS

4.5

Varity_R

0.061

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.056

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over