chr3-190388196-G-A

Position:

chr3-190388196-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_006580.4(CLDN16):c.-134G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

CLDN16
NM_006580.4 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.271

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0070464015).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000519 (79/152272) while in subpopulation AFR AF= 0.00181 (75/41546). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
CLDN16	NM_006580.4 linkuse as main transcript	c.-134G>A	5_prime_UTR_variant	1/5	ENST00000264734.3	NP_006571.2
CLDN16	NM_001378492.1 linkuse as main transcript	c.-93-41G>A	intron_variant			NP_001365421.1
CLDN16	NM_001378493.1 linkuse as main transcript	c.-93-41G>A	intron_variant			NP_001365422.1
CLDN16	XM_047447333.1 linkuse as main transcript	c.-93-41G>A	intron_variant			XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLDN16	ENST00000264734.3 linkuse as main transcript	c.-134G>A	5_prime_UTR_variant	1/5	1	NM_006580.4	ENSP00000264734	P1
CLDN16	ENST00000456423.2 linkuse as main transcript	c.-134G>A	5_prime_UTR_variant	1/2	1		ENSP00000414136
CLDN16	ENST00000468220.1 linkuse as main transcript	n.306+13593G>A	intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000112

AC:

AN:

250888

Hom.:

AF XY:

0.0000959

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000519

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000701

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2021

The c.77G>A (p.G26D) alteration is located in exon 1 (coding exon 1) of the CLDN16 gene. This alteration results from a G to A substitution at nucleotide position 77, causing the glycine (G) at amino acid position 26 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Benign

2.1

DANN

Benign

0.79

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.55

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.16

N;N

REVEL

Benign

0.23

Sift

Benign

0.61

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0020

B;B

Vest4

0.26

MVP

0.72

MPC

0.14

ClinPred

0.016

GERP RS

-3.6

Varity_R

0.042

gMVP

0.094

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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