16-56885328-G-T

Variant names:

• chr16-56885328-G-T
• rs121909384
• NM_001126108.2:c.1889G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001126108.2(SLC12A3):​c.1889G>T​(p.Gly630Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G630G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.76
• Publications: 6 publications found

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SLC12A3 Gene-Disease associations (from GenCC):

• Gitelman syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772
• PP5: Variant 16-56885328-G-T is Pathogenic according to our data. Variant chr16-56885328-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8594.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1889G>T	p.Gly630Val	missense_variant	Exon 15 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1889G>T	p.Gly630Val	missense_variant	Exon 15 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.1886G>T	p.Gly629Val	missense_variant	Exon 15 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1886G>T	p.Gly629Val	missense_variant	Exon 15 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1889G>T	p.Gly630Val	missense_variant	Exon 15 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1889G>T	p.Gly630Val	missense_variant	Exon 15 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1886G>T	p.Gly629Val	missense_variant	Exon 15 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1886G>T	p.Gly629Val	missense_variant	Exon 15 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1403062 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692430

African (AFR) AF: 0.00 AC: 0 AN: 31792

American (AMR) AF: 0.00 AC: 0 AN: 36194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 36128

South Asian (SAS) AF: 0.00 AC: 0 AN: 79382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081032

Other (OTH) AF: 0.00 AC: 0 AN: 58150

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:1

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;D;D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.0	.;L;L;.
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.0
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Vest4		0.87
ClinPred		0.83	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.82
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909384; hg19: chr16-56919240;