rs863224920

Positions:

• chr15-48229199-C-G
• chr15-48229199-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000338.3(SLC12A1):​c.735C>G​(p.Tyr245*) 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 no classification for the single variant (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC12A1 NM_000338.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.735C>G	p.Tyr245*	stop_gained	6/27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.735C>G	p.Tyr245*	stop_gained	6/27		NP_001171761.1
SLC12A1	NM_001384136.1	c.735C>G	p.Tyr245*	stop_gained	6/27		NP_001371065.1
LOC128966560	XR_932204.4	n.222+757G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.735C>G	p.Tyr245*	stop_gained	6/27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.94, 0.95, 0.98
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224920; hg19: chr15-48521396;