16-56894555-T-G

Variant names:

• chr16-56894555-T-G
• rs185927948
• NM_001126108.2:c.2546T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_001126108.2(SLC12A3):​c.2546T>G​(p.Leu849Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L849H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56894555-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 225470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2546T>G	p.Leu849Arg	missense_variant	Exon 22 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2573T>G	p.Leu858Arg	missense_variant	Exon 22 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.2570T>G	p.Leu857Arg	missense_variant	Exon 22 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.2543T>G	p.Leu848Arg	missense_variant	Exon 22 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2546T>G	p.Leu849Arg	missense_variant	Exon 22 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2573T>G	p.Leu858Arg	missense_variant	Exon 22 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2570T>G	p.Leu857Arg	missense_variant	Exon 22 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2543T>G	p.Leu848Arg	missense_variant	Exon 22 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Pathogenic	3.2	.;.;M;.
PhyloP100		7.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.97
MutPred		0.76		.;.;Gain of methylation at L849 (P = 0.0336);.;
MVP		0.97
MPC		0.56
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.96

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

Other links and lift over

dbSNP: rs185927948; hg19: chr16-56928467;