16-56879168-A-G

Variant names:

• chr16-56879168-A-G
• rs200817545
• NM_001126108.2:c.1276A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1 PM2 PM5 PP2 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. 16/22 in silico tools predict a benign 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. N426Y) has been classified as Pathogenic.

• 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
• Publications: 3 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 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr16-56879168-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 403666.Status of the report is no_assertion_criteria_provided, 0 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03483051).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.1276A>G	p.Asn426Asp	missense	Exon 10 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1276A>G	p.Asn426Asp	missense	Exon 10 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1273A>G	p.Asn425Asp	missense	Exon 10 of 26	NP_001119579.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1276A>G	p.Asn426Asp	missense	Exon 10 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1276A>G	p.Asn426Asp	missense	Exon 10 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1273A>G	p.Asn425Asp	missense	Exon 10 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000162 AC: 40 AN: 247430 AF XY: 0.000134

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.000712 AC: 37 AN: 51966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111822

Other (OTH) AF: 0.0000996 AC: 6 AN: 60260

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000412 Hom.: 0

ExAC AF: 0.00111 AC: 135

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N
PhyloP100		5.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Polyphen		0.0030	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

Other links and lift over

dbSNP: rs200817545; hg19: chr16-56913080;