15-48229719-T-C

Variant names:

• chr15-48229719-T-C
• rs3784614
• NM_000338.3:c.864+391T>C

Variant summary

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

The NM_000338.3(SLC12A1):​c.864+391T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 152,270 control chromosomes in the GnomAD database, including 66,679 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 0.93 (66679 hom., cov: 33)
• Consequence: SLC12A1 NM_000338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 1 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):

• antenatal Bartter syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Bartter disease type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

LOC128966560 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	NM_000338.3	MANE Select	c.864+391T>C		intron	N/A	NP_000329.2	Q13621-1
	SLC12A1	NM_001184832.2		c.864+391T>C		intron	N/A	NP_001171761.1	Q13621-3
	SLC12A1	NM_001384136.1		c.864+391T>C		intron	N/A	NP_001371065.1	A0A8I5KSK6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A1	ENST00000380993.8	TSL:5 MANE Select	c.864+391T>C		intron	N/A	ENSP00000370381.3	Q13621-1
	SLC12A1	ENST00000330289.10	TSL:1	c.864+391T>C		intron	N/A	ENSP00000331550.6	Q8IUN5
	SLC12A1	ENST00000558252.5	TSL:1	n.4987+391T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.932 AC: 141771 AN: 152152 Hom.: 66640 Cov.: 33

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.993

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.946

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

GnomAD4 genome AF: 0.932 AC: 141867 AN: 152270 Hom.: 66679 Cov.: 33 AF XY: 0.930 AC XY: 69269 AN XY: 74448

African (AFR) AF: 0.834 AC: 34633 AN: 41512

American (AMR) AF: 0.956 AC: 14635 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3464 AN: 3472

East Asian (EAS) AF: 0.652 AC: 3375 AN: 5180

South Asian (SAS) AF: 0.952 AC: 4580 AN: 4812

European-Finnish (FIN) AF: 0.993 AC: 10556 AN: 10626

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67461 AN: 68042

Other (OTH) AF: 0.947 AC: 2001 AN: 2114

Alfa AF: 0.969 Hom.: 135063

Bravo AF: 0.925

Asia WGS AF: 0.828 AC: 2876 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		-0.010
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: rs3784614; hg19: chr15-48521916;