3-190388282-AGG-AG

Position:

• chr3-190388282-AGG-AG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006580.4(CLDN16):​c.-45delG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,800 control chromosomes in the GnomAD database, including 41,133 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3025 hom., cov: 27)
  • Exomes 𝑓: 0.22 (38108 hom.)
• Consequence: CLDN16 NM_006580.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.808

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 3-190388282-AG-A is Benign according to our data. Variant chr3-190388282-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 282608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-190388282-AG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN16	NM_006580.4	c.-45delG		5_prime_UTR_variant	1/5	ENST00000264734.3	NP_006571.2
CLDN16	NM_001378492.1	c.-45delG		5_prime_UTR_variant	5/9		NP_001365421.1
CLDN16	NM_001378493.1	c.-45delG		5_prime_UTR_variant	4/8		NP_001365422.1
CLDN16	XM_047447333.1	c.-45delG		5_prime_UTR_variant	3/7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000264734	c.-45delG		5_prime_UTR_variant	1/5	1	NM_006580.4	ENSP00000264734.3
CLDN16	ENST00000456423.2	c.-45delG		5_prime_UTR_variant	1/2	1		ENSP00000414136.2
CLDN16	ENST00000468220.1	n.306+13682delG		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28236 AN: 151936 Hom.: 3026 Cov.: 27

Gnomad AFR AF: 0.0905

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.193 AC: 48452 AN: 250984 Hom.: 5424 AF XY: 0.200 AC XY: 27178 AN XY: 135642

Gnomad AFR exome AF: 0.0857

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.0199

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.222 AC: 324459 AN: 1461746 Hom.: 38108 Cov.: 27 AF XY: 0.222 AC XY: 161306 AN XY: 727184

Gnomad4 AFR exome AF: 0.0869

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.0291

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.186 AC: 28248 AN: 152054 Hom.: 3025 Cov.: 27 AF XY: 0.186 AC XY: 13792 AN XY: 74308

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.0265

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.208

Alfa AF: 0.226 Hom.: 714

Bravo AF: 0.172

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hypomagnesemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2016	p.Arg56fs in exon 1 of CLDN16: This variant is not expected to have clinical sig nificance because it has been identified in 25% (16723/66656) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) . This variant only occurs in cis with c.166G>C to create combined c.165_166del insC variant. Variant has ~19% MAF. Gene uses a downstream start site (Met71) -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2020	- -

Computational scores

Source: dbNSFP v4.3

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: rs368234054; hg19: chr3-190106071;