chr3-190388282-AG-A

Variant names:

• chr3-190388282-AG-A
• rs368234054
• NM_006580.4:c.-45delG

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000297357 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 282608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	NM_006580.4	MANE Select	c.-45delG		5_prime_UTR	Exon 1 of 5	NP_006571.2
	CLDN16	NM_001378492.1		c.-45delG		5_prime_UTR	Exon 5 of 9	NP_001365421.1
	CLDN16	NM_001378493.1		c.-45delG		5_prime_UTR	Exon 4 of 8	NP_001365422.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000264734.3	TSL:1 MANE Select	c.-45delG		5_prime_UTR	Exon 1 of 5	ENSP00000264734.3
	CLDN16	ENST00000456423.2	TSL:1	c.-45delG		5_prime_UTR	Exon 1 of 2	ENSP00000414136.2
	ENSG00000297357	ENST00000747317.1		n.268delC		non_coding_transcript_exon	Exon 1 of 2

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

GnomAD2 exomes AF: 0.193 AC: 48452 AN: 250984 AF XY: 0.200

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 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

African (AFR) AF: 0.0869 AC: 2908 AN: 33478

American (AMR) AF: 0.113 AC: 5066 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7142 AN: 26134

East Asian (EAS) AF: 0.0291 AC: 1154 AN: 39694

South Asian (SAS) AF: 0.172 AC: 14802 AN: 86256

European-Finnish (FIN) AF: 0.253 AC: 13494 AN: 53414

Middle Eastern (MID) AF: 0.271 AC: 1560 AN: 5766

European-Non Finnish (NFE) AF: 0.239 AC: 265300 AN: 1111894

Other (OTH) AF: 0.216 AC: 13033 AN: 60392

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

African (AFR) AF: 0.0907 AC: 3764 AN: 41522

American (AMR) AF: 0.174 AC: 2665 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3468

East Asian (EAS) AF: 0.0265 AC: 137 AN: 5176

South Asian (SAS) AF: 0.168 AC: 809 AN: 4826

European-Finnish (FIN) AF: 0.256 AC: 2707 AN: 10560

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16544 AN: 67916

Other (OTH) AF: 0.208 AC: 439 AN: 2114

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Sep 14, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 11, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=130/70	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: rs368234054; hg19: chr3-190106071; COSMIC: COSV53226770;