chr15-48255779-T-C

Variant names:

• chr15-48255779-T-C
• rs2291340
• NM_000338.3:c.1943-32T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000338.3(SLC12A1):​c.1943-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,388,998 control chromosomes in the GnomAD database, including 49,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (13450 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35975 hom.)
• Consequence: SLC12A1 NM_000338.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.898
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-48255779-T-C is Benign according to our data. Variant chr15-48255779-T-C is described in ClinVar as Benign. ClinVar VariationId is 1278170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 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.1943-32T>C		intron	N/A	NP_000329.2
	SLC12A1	NM_001184832.2		c.1943-32T>C		intron	N/A	NP_001171761.1
	SLC12A1	NM_001384136.1		c.1943-32T>C		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.1943-32T>C		intron	N/A	ENSP00000370381.3
	SLC12A1	ENST00000558252.5	TSL:1	n.6066-32T>C		intron	N/A
	SLC12A1	ENST00000560692.5	TSL:1	n.6082-32T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53937 AN: 152012 Hom.: 13404 Cov.: 32

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.268 AC: 50824 AN: 189442 AF XY: 0.257

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.221 AC: 272929 AN: 1236868 Hom.: 35975 Cov.: 16 AF XY: 0.219 AC XY: 135936 AN XY: 619978

African (AFR) AF: 0.722 AC: 20897 AN: 28930

American (AMR) AF: 0.299 AC: 11328 AN: 37904

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 5444 AN: 24054

East Asian (EAS) AF: 0.451 AC: 16627 AN: 36836

South Asian (SAS) AF: 0.232 AC: 17593 AN: 75792

European-Finnish (FIN) AF: 0.220 AC: 11230 AN: 50960

Middle Eastern (MID) AF: 0.275 AC: 1481 AN: 5382

European-Non Finnish (NFE) AF: 0.190 AC: 175176 AN: 924140

Other (OTH) AF: 0.249 AC: 13153 AN: 52870

GnomAD4 genome AF: 0.355 AC: 54047 AN: 152130 Hom.: 13450 Cov.: 32 AF XY: 0.352 AC XY: 26172 AN XY: 74376

African (AFR) AF: 0.703 AC: 29179 AN: 41488

American (AMR) AF: 0.295 AC: 4509 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 792 AN: 3462

East Asian (EAS) AF: 0.424 AC: 2193 AN: 5168

South Asian (SAS) AF: 0.256 AC: 1237 AN: 4830

European-Finnish (FIN) AF: 0.208 AC: 2197 AN: 10586

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13097 AN: 68000

Other (OTH) AF: 0.337 AC: 709 AN: 2102

Alfa AF: 0.227 Hom.: 3209

Bravo AF: 0.377

Asia WGS AF: 0.389 AC: 1351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.74
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2291340; hg19: chr15-48547976; COSMIC: COSV66795023;