15-48247390-T-G

Variant names:

• chr15-48247390-T-G
• NM_000338.3:c.1614T>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000338.3(SLC12A1):​c.1614T>G​(p.Tyr538*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y538Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC12A1 NM_000338.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.214

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48247390-T-G is Pathogenic according to our data. Variant chr15-48247390-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2692633.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.1614T>G	p.Tyr538*	stop_gained	Exon 13 of 27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.1614T>G	p.Tyr538*	stop_gained	Exon 13 of 27		NP_001171761.1
SLC12A1	NM_001384136.1	c.1614T>G	p.Tyr538*	stop_gained	Exon 13 of 27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.1614T>G	p.Tyr538*	stop_gained	Exon 13 of 27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr538*) in the SLC12A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A1 are known to be pathogenic (PMID: 8640224, 9585600, 19096086). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bartter syndrome type I (PMID: 27748541). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.64	D
Vest4		0.96, 0.96
GERP RS		-4.5

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-48539587;