rs1552311

Positions:

• chr15-48288516-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000338.3(SLC12A1):​c.2873T>C​(p.Val958Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,432,578 control chromosomes in the GnomAD database, including 715,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75778 hom., cov: 31)
  • Exomes 𝑓: 1.0 (639798 hom.)
• Consequence: SLC12A1 NM_000338.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002561
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.777

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.747869E-7).
• BP6: Variant 15-48288516-T-C is Benign according to our data. Variant chr15-48288516-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48288516-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27		NP_001171761.1
SLC12A1	NM_001384136.1	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.2873T>C	p.Val958Ala	missense_variant, splice_region_variant	23/27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151817 AN: 152196 Hom.: 75720 Cov.: 31

Gnomad AFR AF: 0.991

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.996

GnomAD3 exomes AF: 0.999 AC: 160933 AN: 161024 Hom.: 80422 AF XY: 1.00 AC XY: 84015 AN XY: 84050

Gnomad AFR exome AF: 0.992

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 1.00 AC: 1279929 AN: 1280264 Hom.: 639798 Cov.: 19 AF XY: 1.00 AC XY: 637983 AN XY: 638128

Gnomad4 AFR exome AF: 0.991

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.999

GnomAD4 genome AF: 0.998 AC: 151934 AN: 152314 Hom.: 75778 Cov.: 31 AF XY: 0.998 AC XY: 74287 AN XY: 74472

Gnomad4 AFR AF: 0.991

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.996

Alfa AF: 0.999 Hom.: 112512

Bravo AF: 0.997

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.992 AC: 4335

ESP6500EA AF: 1.00 AC: 8510

ExAC AF: 0.998 AC: 92168

Asia WGS AF: 0.999 AC: 3474 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2016	This is a RefSeq error. The reference base (c.2873T) is the minor allele. This a llele (T) has been identified in 0.62% (21/3400) of African chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs15523 11) and thus meets criteria to be classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bartter disease type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.22
DEOGEN2	Benign	0.13	.;.;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.12	.;T;.;.;T;T
MetaRNN	Benign	5.7e-7	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.0	N;.;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.8	.;.;.;N;N;N
REVEL	Benign	0.21
Sift	Benign	1.0	.;.;.;T;T;T
Sift4G	Benign	0.81	.;.;.;T;T;T
Polyphen		0.0	.;.;B;B;B;.
Vest4		0.026, 0.024
MPC		0.17
ClinPred		0.0083	T
GERP RS		4.5
Varity_R		0.023
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.050
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: rs1552311; hg19: chr15-48580713;