chr3-190388453-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

renal hypomagnesemia 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

CLDN16 links:

ENSG00000297357 (HGNC:):

ENSG00000297357 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 260004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CLDN16	NM_006580.4 link	c.114+10T>C	intron_variant	Intron 1 of 4	ENST00000264734.3	NP_006571.2
CLDN16	NM_001378492.1 link	c.114+10T>C	intron_variant	Intron 5 of 8		NP_001365421.1
CLDN16	NM_001378493.1 link	c.114+10T>C	intron_variant	Intron 4 of 7		NP_001365422.1
CLDN16	XM_047447333.1 link	c.114+10T>C	intron_variant	Intron 3 of 6		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CLDN16	ENST00000264734.3 link	c.114+10T>C	intron_variant	Intron 1 of 4	1	NM_006580.4	ENSP00000264734.3
CLDN16	ENST00000456423.2 link	c.114+10T>C	intron_variant	Intron 1 of 1	1		ENSP00000414136.2
ENSG00000297357	ENST00000747317.1 link	n.98A>G	non_coding_transcript_exon_variant	Exon 1 of 2
CLDN16	ENST00000468220.1 link	n.306+13850T>C	intron_variant	Intron 3 of 4	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

GnomAD2 exomes

AF:

0.193

AC:

48331

AN:

250268

AF XY:

0.200

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 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

African (AFR)

AF:

0.0866

AC:

2898

AN:

33446

American (AMR)

AF:

0.113

AC:

5067

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

7140

AN:

26124

East Asian (EAS)

AF:

0.0291

AC:

1155

AN:

39698

South Asian (SAS)

AF:

0.172

AC:

14805

AN:

86230

European-Finnish (FIN)

AF:

0.253

AC:

13491

AN:

53392

Middle Eastern (MID)

AF:

0.270

AC:

1558

AN:

5764

European-Non Finnish (NFE)

AF:

0.238

AC:

264603

AN:

1110250

Other (OTH)

AF:

0.216

AC:

13005

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

12053

24106

36159

48212

60265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8746

17492

26238

34984

43730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.186

AC:

28360

AN:

152138

Hom.:

3085

Cov.:

AF XY:

0.186

AC XY:

13860

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0908

AC:

3772

AN:

41542

American (AMR)

AF:

0.174

AC:

2663

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

935

AN:

3472

East Asian (EAS)

AF:

0.0265

AC:

137

AN:

5170

South Asian (SAS)

AF:

0.168

AC:

809

AN:

4822

European-Finnish (FIN)

AF:

0.259

AC:

2740

AN:

10584

Middle Eastern (MID)

AF:

0.291

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.244

AC:

16613

AN:

67962

Other (OTH)

AF:

0.208

AC:

437

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1138

2277

3415

4554

5692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.209

Hom.:

1186

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

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) .

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.2

(source)

DANN

Benign

0.65

PhyloP100

-0.16

PromoterAI

0.021

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over