rs141106709

chr15-48226555-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000338.3(SLC12A1):c.708C>T(p.Asn236=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,606,322 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: SLC12A1 NM_000338.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.04

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 15-48226555-C-T is Benign according to our data. Variant chr15-48226555-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 448390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48226555-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.05 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A1	NM_000338.3	c.708C>T	p.Asn236=	synonymous_variant	5/27	ENST00000380993.8
SLC12A1	NM_001184832.2	c.629-524C>T		intron_variant
SLC12A1	NM_001384136.1	c.724+608C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A1	ENST00000380993.8	c.708C>T	p.Asn236=	synonymous_variant	5/27	5	NM_000338.3	A1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00751

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000855 AC: 210 AN: 245692 Hom.: 0 AF XY: 0.000810 AC XY: 108 AN XY: 133316

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00733

Gnomad SAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000456 AC: 663 AN: 1454034 Hom.: 0 Cov.: 28 AF XY: 0.000410 AC XY: 297 AN XY: 723526

Gnomad4 AFR exome AF: 0.0000904

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00671

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.000665

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74478

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00753

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000608

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000166

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 09, 2017

- -

Bartter disease type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
Cadd	Benign	13
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs141106709; hg19: chr15-48518752; COSMIC: COSV57709051;