16-56879168-A-G

Position:

• chr16-56879168-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001126108.2(SLC12A3):​c.1276A>G​(p.Asn426Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity S12A3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03483051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1276A>G	p.Asn426Asp	missense_variant	10/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1276A>G	p.Asn426Asp	missense_variant	10/26		NP_000330.3
SLC12A3	NM_001126107.2	c.1273A>G	p.Asn425Asp	missense_variant	10/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1273A>G	p.Asn425Asp	missense_variant	10/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1276A>G	p.Asn426Asp	missense_variant	10/26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1276A>G	p.Asn426Asp	missense_variant	10/26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1273A>G	p.Asn425Asp	missense_variant	10/26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1273A>G	p.Asn425Asp	missense_variant	10/26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.000162 AC: 40 AN: 247430 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134634

Gnomad AFR exome AF: 0.000448

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.000387

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.000283

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.000333

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000336 AC: 49 AN: 1459980 Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 31 AN XY: 726366

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome Cov.: 32

ExAC AF: 0.00111 AC: 135

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.53
DEOGEN2	Uncertain	0.47	.;.;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	.;N;N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0030	B;B;B;.
Vest4		0.21
MVP		0.79
MPC		0.11
ClinPred		0.018	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.73

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: rs200817545; hg19: chr16-56913080;