15-48207584-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000338.3(SLC12A1):c.-136A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 579,698 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (504 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (160 hom.)
• Consequence: SLC12A1 NM_000338.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 15-48207584-A-G is Benign according to our data. Variant chr15-48207584-A-G is described in ClinVar as [Benign]. Clinvar id is 316250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A1	NM_000338.3	c.-136A>G		5_prime_UTR_variant	2/27	ENST00000380993.8
SLC12A1	NM_001184832.2	c.-136A>G		5_prime_UTR_variant	2/27
SLC12A1	NM_001384136.1	c.-136A>G		5_prime_UTR_variant	2/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A1	ENST00000380993.8	c.-136A>G		5_prime_UTR_variant	2/27	5	NM_000338.3	A1

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6753 AN: 152164 Hom.: 506 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.00549 AC: 2345 AN: 427416 Hom.: 160 Cov.: 6 AF XY: 0.00474 AC XY: 1033 AN XY: 217786

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.00864

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000284

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000907

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0444 AC: 6761 AN: 152282 Hom.: 504 Cov.: 32 AF XY: 0.0419 AC XY: 3121 AN XY: 74470

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0205 Hom.: 38

Bravo AF: 0.0507

Asia WGS AF: 0.00780 AC: 27 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartter disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	9.0
Dann	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs35787656; hg19: chr15-48499781;