3-190388285-G-C

Variant names:

• chr3-190388285-G-C
• rs3214506
• NM_006580.4:c.-45G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006580.4(CLDN16):​c.-45G>C 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 1,613,798 control chromosomes in the GnomAD database, including 41,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3026 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38108 hom.)
• Consequence: CLDN16 NM_006580.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0520

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047626793).
• BP6: Variant 3-190388285-G-C is Benign according to our data. Variant chr3-190388285-G-C is described in ClinVar as [Benign]. Clinvar id is 344445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-190388285-G-C 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 rank	MANE	Protein	UniProt
CLDN16	NM_006580.4	c.-45G>C		5_prime_UTR_variant	Exon 1 of 5	ENST00000264734.3	NP_006571.2
CLDN16	NM_001378492.1	c.-45G>C		5_prime_UTR_variant	Exon 5 of 9		NP_001365421.1
CLDN16	NM_001378493.1	c.-45G>C		5_prime_UTR_variant	Exon 4 of 8		NP_001365422.1
CLDN16	XM_047447333.1	c.-45G>C		5_prime_UTR_variant	Exon 3 of 7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000264734	c.-45G>C		5_prime_UTR_variant	Exon 1 of 5	1	NM_006580.4	ENSP00000264734.3
CLDN16	ENST00000456423	c.-45G>C		5_prime_UTR_variant	Exon 1 of 2	1		ENSP00000414136.2
CLDN16	ENST00000468220.1	n.306+13682G>C		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28239 AN: 151932 Hom.: 3027 Cov.: 32

Gnomad AFR AF: 0.0905

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0263

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.193 AC: 48454 AN: 250974 Hom.: 5424 AF XY: 0.200 AC XY: 27178 AN XY: 135632

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: 324468 AN: 1461748 Hom.: 38108 Cov.: 34 AF XY: 0.222 AC XY: 161310 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: 28251 AN: 152050 Hom.: 3026 Cov.: 32 AF XY: 0.186 AC XY: 13794 AN XY: 74298

Gnomad4 AFR AF: 0.0906

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.0265

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.208

Alfa AF: 0.230 Hom.: 3157

Bravo AF: 0.172

ExAC AF: 0.194 AC: 23607

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary hypomagnesemia Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala56Pro in exon 1 of CLDN16: This variant is not expected to have clinical si gnificance because it has been identified in 25.09% (16723/66656) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs3214506). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	2.1
DANN	Benign	0.95
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.080	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.13	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.16
MPC		0.14
ClinPred		0.00072	T
GERP RS		-3.9
Varity_R		0.070
gMVP		0.12

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: rs3214506; hg19: chr3-190106074; COSMIC: COSV53226998;