rs2278490

Variant names:

• chr16-56892881-C-T
• rs2278490
• NM_001126108.2:c.2420-72C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-56892881-C-T
• chr16-56892881-C-A
• chr16-56892881-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.2420-72C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,245,246 control chromosomes in the GnomAD database, including 24,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4333 hom., cov: 33)
  • Exomes 𝑓: 0.17 (20332 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04
• Publications: 7 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-56892881-C-T is Benign according to our data. Variant chr16-56892881-C-T is described in ClinVar as Benign. ClinVar VariationId is 1228533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.2420-72C>T		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2447-72C>T		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2444-72C>T		intron	N/A	NP_001119579.2	P55017-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.2420-72C>T		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2447-72C>T		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2444-72C>T		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32948 AN: 152110 Hom.: 4315 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.172 AC: 187453 AN: 1093018 Hom.: 20332 AF XY: 0.172 AC XY: 95963 AN XY: 557894

African (AFR) AF: 0.323 AC: 8394 AN: 26000

American (AMR) AF: 0.355 AC: 14410 AN: 40568

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 3907 AN: 23340

East Asian (EAS) AF: 0.518 AC: 18927 AN: 36538

South Asian (SAS) AF: 0.245 AC: 18716 AN: 76358

European-Finnish (FIN) AF: 0.146 AC: 7508 AN: 51458

Middle Eastern (MID) AF: 0.183 AC: 839 AN: 4594

European-Non Finnish (NFE) AF: 0.135 AC: 105743 AN: 786170

Other (OTH) AF: 0.188 AC: 9009 AN: 47992

GnomAD4 genome AF: 0.217 AC: 32994 AN: 152228 Hom.: 4333 Cov.: 33 AF XY: 0.221 AC XY: 16413 AN XY: 74414

African (AFR) AF: 0.318 AC: 13224 AN: 41542

American (AMR) AF: 0.270 AC: 4136 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 602 AN: 3466

East Asian (EAS) AF: 0.484 AC: 2501 AN: 5166

South Asian (SAS) AF: 0.249 AC: 1202 AN: 4828

European-Finnish (FIN) AF: 0.144 AC: 1533 AN: 10612

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9109 AN: 68002

Other (OTH) AF: 0.222 AC: 469 AN: 2112

Alfa AF: 0.148 Hom.: 2872

Bravo AF: 0.231

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2278490; hg19: chr16-56926793; COSMIC: COSV107283323;