rs34819316

Positions:

• chr15-48208066-G-A
• chr15-48208066-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_000338.3(SLC12A1):​c.347G>A​(p.Arg116His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,613,608 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (30 hom.)
• Consequence: SLC12A1 NM_000338.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:6
• Conservation: PhyloP100: 10.0

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 -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.02112645).
• BP6: Variant 15-48208066-G-A is Benign according to our data. Variant chr15-48208066-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445491.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2, Likely_pathogenic=1}. Variant chr15-48208066-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.347G>A	p.Arg116His	missense_variant	2/27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.347G>A	p.Arg116His	missense_variant	2/27		NP_001171761.1
SLC12A1	NM_001384136.1	c.347G>A	p.Arg116His	missense_variant	2/27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.347G>A	p.Arg116His	missense_variant	2/27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00346 AC: 861 AN: 248770 Hom.: 6 AF XY: 0.00351 AC XY: 472 AN XY: 134606

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00514

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00457 AC: 6680 AN: 1461354 Hom.: 30 Cov.: 31 AF XY: 0.00443 AC XY: 3219 AN XY: 726902

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00483

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00206

Gnomad4 NFE exome AF: 0.00536

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00324 AC: 494 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74426

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00467

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00454 Hom.: 6

Bravo AF: 0.00398

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00334 AC: 405

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00498

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SLC12A1 p.Arg116His variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs34819316) and in ClinVar (classified as a VUS by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was identified in control databases in 955 of 280172 chromosomes (7 homozygous) at a frequency of 0.003409 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 38 of 7182 chromosomes (freq: 0.005291), European (non-Finnish) in 636 of 126808 chromosomes (freq: 0.005015), Ashkenazi Jewish in 49 of 10314 chromosomes (freq: 0.004751), Latino in 161 of 35394 chromosomes (freq: 0.004549), European (Finnish) in 46 of 25056 chromosomes (freq: 0.001836), African in 24 of 24958 chromosomes (freq: 0.000962) and South Asian in 1 of 30510 chromosomes (freq: 0.000033), but was not observed in the East Asian population. The p.Arg116 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2020	This variant is associated with the following publications: (PMID: 20219833, 17699451, 25422309, 31672324) -

Bartter disease type 1 Pathogenic:1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, flagged submission	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 11, 2023	The p.Arg116His variant in SLC12A1 has been classified as likely benign because it has been been identified in 0.5% (636/126808) of European chromosomes, including 7 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.2.1.1). This is frequency is greater than expected for a pathogenic allele in SLC12A to cause Bartter syndrome. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. ACMG/AMP Criteria applied: BS1, PP3. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2022	Variant summary: SLC12A1 c.347G>A (p.Arg116His) results in a non-conservative amino acid change located in the Amino acid permease, N-terminal domain (IPR013612) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 280172 control chromosomes (gnomAD), including 7 homozygotes. The variant was found occurring predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database, with 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC12A1 causing Bartter Syndrome, Type 1 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as VUS, one as likely pathogenic, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

SLC12A1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	.;.;D;D;D;.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.021	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.6	M;.;M;M;M;M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	.;.;.;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.044	.;.;.;D;D;D;D;T
Sift4G	Uncertain	0.045	.;.;.;D;D;D;D;T
Polyphen		0.99, 0.88	.;.;D;D;D;.;P;.
Vest4		0.84, 0.81, 0.80, 0.88, 0.94
MVP		0.95
MPC		0.70
ClinPred		0.047	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.81

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: rs34819316; hg19: chr15-48500263; COSMIC: COSV57708605; COSMIC: COSV57708605;