15-48259183-CTT-CTTT

Variant names:

• chr15-48259183-C-CT
• rs112495679
• NM_000338.3:c.2043-9dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000338.3(SLC12A1):​c.2043-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,528,386 control chromosomes in the GnomAD database, including 1,503 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (184 hom., cov: 31)
  • Exomes 𝑓: 0.043 (1319 hom.)
• Consequence: SLC12A1 NM_000338.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.46
• 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-48259183-C-CT is Benign according to our data. Variant chr15-48259183-C-CT is described in ClinVar as Benign. ClinVar VariationId is 255873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 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.2043-9dupT		splice_region intron	N/A	NP_000329.2	Q13621-1
	SLC12A1	NM_001184832.2		c.2043-9dupT		splice_region intron	N/A	NP_001171761.1	Q13621-3
	SLC12A1	NM_001384136.1		c.2043-9dupT		splice_region 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.2043-17_2043-16insT		intron	N/A	ENSP00000370381.3	Q13621-1
	SLC12A1	ENST00000558252.5	TSL:1	n.6166-17_6166-16insT		intron	N/A
	SLC12A1	ENST00000560692.5	TSL:1	n.6182-17_6182-16insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 6982 AN: 151930 Hom.: 184 Cov.: 31

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0150

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0379

GnomAD2 exomes AF: 0.0373 AC: 9234 AN: 247322 AF XY: 0.0360

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.0513

Gnomad NFE exome AF: 0.0504

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0427 AC: 58747 AN: 1376338 Hom.: 1319 Cov.: 24 AF XY: 0.0421 AC XY: 29006 AN XY: 689638

African (AFR) AF: 0.0537 AC: 1707 AN: 31760

American (AMR) AF: 0.0219 AC: 974 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 602 AN: 25550

East Asian (EAS) AF: 0.000229 AC: 9 AN: 39240

South Asian (SAS) AF: 0.0149 AC: 1259 AN: 84352

European-Finnish (FIN) AF: 0.0533 AC: 2840 AN: 53290

Middle Eastern (MID) AF: 0.0108 AC: 60 AN: 5536

European-Non Finnish (NFE) AF: 0.0473 AC: 48985 AN: 1034716

Other (OTH) AF: 0.0403 AC: 2311 AN: 57356

GnomAD4 genome AF: 0.0460 AC: 6993 AN: 152048 Hom.: 184 Cov.: 31 AF XY: 0.0449 AC XY: 3341 AN XY: 74356

African (AFR) AF: 0.0540 AC: 2239 AN: 41442

American (AMR) AF: 0.0332 AC: 508 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3464

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0152 AC: 73 AN: 4810

European-Finnish (FIN) AF: 0.0485 AC: 514 AN: 10602

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0511 AC: 3473 AN: 67948

Other (OTH) AF: 0.0375 AC: 79 AN: 2106

Alfa AF: 0.0345 Hom.: 38

Bravo AF: 0.0435

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
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: rs112495679; hg19: chr15-48551380;