3-190388453-T-C

Position:

chr3-190388453-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006580.4(CLDN16):c.114+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,612,088 control chromosomes in the GnomAD database, including 41,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3085 hom., cov: 32)

Exomes 𝑓: 0.22 ( 38090 hom. )

Consequence

CLDN16
NM_006580.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.164

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 3-190388453-T-C is Benign according to our data. Variant chr3-190388453-T-C is described in ClinVar as [Benign]. Clinvar id is 260004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-190388453-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CLDN16	NM_006580.4 linkuse as main transcript	c.114+10T>C	intron_variant	ENST00000264734.3	NP_006571.2
CLDN16	NM_001378492.1 linkuse as main transcript	c.114+10T>C	intron_variant		NP_001365421.1
CLDN16	NM_001378493.1 linkuse as main transcript	c.114+10T>C	intron_variant		NP_001365422.1
CLDN16	XM_047447333.1 linkuse as main transcript	c.114+10T>C	intron_variant		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
CLDN16	ENST00000264734.3 linkuse as main transcript	c.114+10T>C	intron_variant	1	NM_006580.4	ENSP00000264734	P1
CLDN16	ENST00000456423.2 linkuse as main transcript	c.114+10T>C	intron_variant	1		ENSP00000414136
CLDN16	ENST00000468220.1 linkuse as main transcript	n.306+13850T>C	intron_variant, non_coding_transcript_variant	4

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28348

AN:

152020

Hom.:

3086

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0907

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.0262

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.293

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.212

GnomAD3 exomes

AF:

0.193

AC:

48331

AN:

250268

Hom.:

5452

AF XY:

0.200

AC XY:

27105

AN XY:

135236

show subpopulations

Gnomad AFR exome

AF:

0.0857

Gnomad AMR exome

AF:

0.110

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.0199

Gnomad SAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.222

AC:

323722

AN:

1459950

Hom.:

38090

Cov.:

AF XY:

0.222

AC XY:

160991

AN XY:

726402

show subpopulations

Gnomad4 AFR exome

AF:

0.0866

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:

0.238

Gnomad4 OTH exome

AF:

0.216

GnomAD4 genome

AF:

0.186

AC:

28360

AN:

152138

Hom.:

3085

Cov.:

AF XY:

0.186

AC XY:

13860

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0908

Gnomad4 AMR

AF:

0.174

Gnomad4 ASJ

AF:

0.269

Gnomad4 EAS

AF:

0.0265

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.259

Gnomad4 NFE

AF:

0.244

Gnomad4 OTH

AF:

0.208

Alfa

AF:

0.211

Hom.:

1185

Bravo

AF:

0.172

Asia WGS

AF:

0.0890

AC:

313

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.324+10T>C in intron 1 of CLDN16: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 25.12% (16730/66596) of European chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1491994) . -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary hypomagnesemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.2

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over