3-190399021-G-C

Variant names:

• chr3-190399021-G-C
• rs17504970
• NM_006580.4:c.115-3316G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006580.4(CLDN16):​c.115-3316G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,096 control chromosomes in the GnomAD database, including 3,055 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3055 hom., cov: 32)
• Consequence: CLDN16 NM_006580.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.177
• Publications: 2 publications found

Genes affected

CLDN16 (HGNC:2037): (claudin 16) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]

CLDN16 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 3

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006580.4. 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
	CLDN16	NM_006580.4	MANE Select	c.115-3316G>C		intron	N/A	NP_006571.2	Q9Y5I7
	CLDN16	NM_001378492.1		c.115-3316G>C		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.115-3316G>C		intron	N/A	NP_001365422.1	Q9Y5I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000264734.3	TSL:1 MANE Select	c.115-3316G>C		intron	N/A	ENSP00000264734.3	Q9Y5I7
	CLDN16	ENST00000456423.2	TSL:1	c.114+10578G>C		intron	N/A	ENSP00000414136.2	F6SGM4
	CLDN16	ENST00000880223.1		c.115-3316G>C		intron	N/A	ENSP00000550282.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28197 AN: 151978 Hom.: 3056 Cov.: 32

Gnomad AFR AF: 0.0906

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.292

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.210

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.185 AC: 28209 AN: 152096 Hom.: 3055 Cov.: 32 AF XY: 0.185 AC XY: 13786 AN XY: 74350

African (AFR) AF: 0.0907 AC: 3764 AN: 41498

American (AMR) AF: 0.173 AC: 2637 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 934 AN: 3470

East Asian (EAS) AF: 0.0263 AC: 136 AN: 5176

South Asian (SAS) AF: 0.167 AC: 806 AN: 4820

European-Finnish (FIN) AF: 0.259 AC: 2732 AN: 10564

Middle Eastern (MID) AF: 0.290 AC: 84 AN: 290

European-Non Finnish (NFE) AF: 0.243 AC: 16510 AN: 67972

Other (OTH) AF: 0.206 AC: 435 AN: 2112

Alfa AF: 0.126 Hom.: 210

Bravo AF: 0.172

Asia WGS AF: 0.0880 AC: 311 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.4
DANN	Benign	0.60
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17504970; hg19: chr3-190116810;