NM_000338.3:c.2486-4668A>G

Variant names:

• chr15-48280438-A-G
• rs8039653
• NM_000338.3:c.2486-4668A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000338.3(SLC12A1):​c.2486-4668A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 152,042 control chromosomes in the GnomAD database, including 5,343 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 0.25 (5343 hom., cov: 32)
• Consequence: SLC12A1 NM_000338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 3 publications found

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

ENSG00000309916 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	NM_000338.3	MANE Select	c.2486-4668A>G		intron	N/A	NP_000329.2
	SLC12A1	NM_001184832.2		c.2486-4668A>G		intron	N/A	NP_001171761.1
	SLC12A1	NM_001384136.1		c.2486-4668A>G		intron	N/A	NP_001371065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	ENST00000380993.8	TSL:5 MANE Select	c.2486-4668A>G		intron	N/A	ENSP00000370381.3
	SLC12A1	ENST00000558252.5	TSL:1	n.6609-4668A>G		intron	N/A
	SLC12A1	ENST00000560692.5	TSL:1	n.6625-4668A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37300 AN: 151924 Hom.: 5319 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.251

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.246 AC: 37367 AN: 152042 Hom.: 5343 Cov.: 32 AF XY: 0.246 AC XY: 18293 AN XY: 74368

African (AFR) AF: 0.371 AC: 15352 AN: 41424

American (AMR) AF: 0.257 AC: 3930 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 752 AN: 3468

East Asian (EAS) AF: 0.412 AC: 2130 AN: 5172

South Asian (SAS) AF: 0.231 AC: 1114 AN: 4824

European-Finnish (FIN) AF: 0.193 AC: 2049 AN: 10590

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11387 AN: 67960

Other (OTH) AF: 0.258 AC: 545 AN: 2114

Alfa AF: 0.199 Hom.: 4116

Bravo AF: 0.256

Asia WGS AF: 0.362 AC: 1258 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.42
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8039653; hg19: chr15-48572635;