rs2279368

Variant names:

• chr15-48250096-T-A
• rs2279368
• NM_000338.3:c.1786+420T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000338.3(SLC12A1):​c.1786+420T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,178 control chromosomes in the GnomAD database, including 2,885 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 0.14 (2885 hom., cov: 32)
• Consequence: SLC12A1 NM_000338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.1786+420T>A		intron_variant	Intron 14 of 26	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.1786+420T>A		intron_variant	Intron 14 of 26		NP_001171761.1
SLC12A1	NM_001384136.1	c.1786+420T>A		intron_variant	Intron 14 of 26		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.1786+420T>A		intron_variant	Intron 14 of 26	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21015 AN: 152060 Hom.: 2878 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0892

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.0741

Gnomad FIN AF: 0.0739

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0373

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.138 AC: 21061 AN: 152178 Hom.: 2885 Cov.: 32 AF XY: 0.138 AC XY: 10286 AN XY: 74420

African (AFR) AF: 0.341 AC: 14113 AN: 41442

American (AMR) AF: 0.0893 AC: 1366 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3468

East Asian (EAS) AF: 0.305 AC: 1583 AN: 5182

South Asian (SAS) AF: 0.0742 AC: 358 AN: 4826

European-Finnish (FIN) AF: 0.0739 AC: 785 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0373 AC: 2539 AN: 68028

Other (OTH) AF: 0.101 AC: 214 AN: 2112

Alfa AF: 0.0953 Hom.: 204

Bravo AF: 0.148

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.70
PhyloP100		2.2
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: rs2279368; hg19: chr15-48542293;