chr3-190346425-A-G

Variant names:

• chr3-190346425-A-G
• rs3909582
• NM_001378492.1:c.-278-24468A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378492.1(CLDN16):​c.-278-24468A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,188 control chromosomes in the GnomAD database, including 1,563 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1563 hom., cov: 32)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_001378492.1	c.-278-24468A>G		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-278-24468A>G		intron_variant	Intron 1 of 7		NP_001365422.1
CLDN16	XM_047447333.1	c.-170+23764A>G		intron_variant	Intron 1 of 6		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000468220.1	n.121+23764A>G		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19652 AN: 152068 Hom.: 1563 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0872

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.122

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.129 AC: 19673 AN: 152188 Hom.: 1563 Cov.: 32 AF XY: 0.126 AC XY: 9367 AN XY: 74410

African (AFR) AF: 0.220 AC: 9142 AN: 41484

American (AMR) AF: 0.112 AC: 1709 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3470

East Asian (EAS) AF: 0.0868 AC: 450 AN: 5184

South Asian (SAS) AF: 0.135 AC: 653 AN: 4824

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10608

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.0937 AC: 6371 AN: 68018

Other (OTH) AF: 0.122 AC: 259 AN: 2116

Alfa AF: 0.109 Hom.: 624

Bravo AF: 0.139

Asia WGS AF: 0.114 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.86
DANN	Benign	0.72
PhyloP100		-0.29

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3909582; hg19: chr3-190064214;