15-48251711-C-T

Variant names:

• chr15-48251711-C-T
• NM_000338.3:c.1883C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000338.3(SLC12A1):​c.1883C>T​(p.Ala628Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC12A1 NM_000338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.1883C>T	p.Ala628Val	missense_variant	Exon 15 of 27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.1883C>T	p.Ala628Val	missense_variant	Exon 15 of 27		NP_001171761.1
SLC12A1	NM_001384136.1	c.1883C>T	p.Ala628Val	missense_variant	Exon 15 of 27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.1883C>T	p.Ala628Val	missense_variant	Exon 15 of 27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;.;D;.;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;.;D;.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.;H;.;H;H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	.;.;.;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	.;.;.;D;D;D;D
Sift4G	Uncertain	0.0020	.;.;.;D;D;D;D
Polyphen		0.99	.;.;D;.;D;D;.
Vest4		0.92, 0.91
MutPred		0.82		Gain of glycosylation at T631 (P = 0.123);.;Gain of glycosylation at T631 (P = 0.123);.;Gain of glycosylation at T631 (P = 0.123);Gain of glycosylation at T631 (P = 0.123);Gain of glycosylation at T631 (P = 0.123);
MVP		0.99
MPC		0.56
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.73
gMVP		0.91

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: chr15-48543908;