3-190322608-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378492.1(CLDN16):c.-279+7549C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 292,708 control chromosomes in the GnomAD database, including 36,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20136 hom., cov: 33)

Exomes 𝑓: 0.47 ( 16061 hom. )

Consequence

CLDN16
NM_001378492.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.94

Publications

7 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 links:

CLDN1 (HGNC:2032): (claudin 1) 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. Loss of function mutations result in neonatal ichthyosis-sclerosing cholangitis syndrome. [provided by RefSeq, Jul 2008]

CLDN1 Gene-Disease associations (from GenCC):

neonatal ichthyosis-sclerosing cholangitis syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

CLDN1 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=-0.74).

BP6

Variant 3-190322608-C-T is Benign according to our data. Variant chr3-190322608-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLDN16	NM_001378492.1		c.-279+7549C>T	intron	N/A	NP_001365421.1	Q9Y5I7
CLDN16	NM_001378493.1		c.-279+32017C>T	intron	N/A	NP_001365422.1	Q9Y5I7
CLDN1	NM_021101.5	MANE Select	c.-402G>A	upstream_gene	N/A	NP_066924.1	O95832

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
CLDN16	ENST00000880223.1	c.-332C>T	5_prime_UTR	Exon 1 of 8	ENSP00000550282.1
CLDN16	ENST00000880225.1	c.-355C>T	5_prime_UTR	Exon 1 of 8	ENSP00000550284.1
CLDN16	ENST00000880227.1	c.-147C>T	5_prime_UTR	Exon 1 of 6	ENSP00000550286.1

Frequencies

GnomAD3 genomes

AF:

0.511

AC:

77626

AN:

151892

Hom.:

20138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.581

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.466

Gnomad EAS

AF:

0.696

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.471

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.474

Gnomad OTH

AF:

0.497

GnomAD4 exome

AF:

0.470

AC:

66086

AN:

140698

Hom.:

16061

Cov.:

AF XY:

0.458

AC XY:

34334

AN XY:

74988

show subpopulations

African (AFR)

AF:

0.574

AC:

941

AN:

1640

American (AMR)

AF:

0.549

AC:

2508

AN:

4566

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

1559

AN:

3234

East Asian (EAS)

AF:

0.729

AC:

3342

AN:

4582

South Asian (SAS)

AF:

0.371

AC:

9014

AN:

24296

European-Finnish (FIN)

AF:

0.468

AC:

4080

AN:

8714

Middle Eastern (MID)

AF:

0.443

AC:

239

AN:

540

European-Non Finnish (NFE)

AF:

0.476

AC:

40749

AN:

85536

Other (OTH)

AF:

0.481

AC:

3654

AN:

7590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

1640

3280

4919

6559

8199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.511

AC:

77653

AN:

152010

Hom.:

20136

Cov.:

AF XY:

0.508

AC XY:

37780

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.581

AC:

24089

AN:

41480

American (AMR)

AF:

0.498

AC:

7616

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.466

AC:

1614

AN:

3466

East Asian (EAS)

AF:

0.695

AC:

3553

AN:

5110

South Asian (SAS)

AF:

0.372

AC:

1794

AN:

4818

European-Finnish (FIN)

AF:

0.471

AC:

4981

AN:

10580

Middle Eastern (MID)

AF:

0.575

AC:

169

AN:

294

European-Non Finnish (NFE)

AF:

0.474

AC:

32204

AN:

67942

Other (OTH)

AF:

0.496

AC:

1047

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1970

3939

5909

7878

9848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.524

Hom.:

7707

Bravo

AF:

0.523

Asia WGS

AF:

0.540

AC:

1875

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.8

(source)

DANN

Benign

0.87

PhyloP100

-1.9

PromoterAI

0.064

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over