rs16865373

Variant names:

• chr3-190329019-C-T
• rs16865373
• NM_001378492.1:c.-279+13960C>T

Variant summary

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

The NM_001378492.1(CLDN16):​c.-279+13960C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 152,280 control chromosomes in the GnomAD database, including 204 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 0.046 (204 hom., cov: 32)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_001378492.1	c.-279+13960C>T		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+38428C>T		intron_variant	Intron 1 of 7		NP_001365422.1
CLDN16	XM_047447333.1	c.-170+6358C>T		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+6358C>T		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6977 AN: 152162 Hom.: 203 Cov.: 32

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0537

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0468

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

GnomAD4 genome AF: 0.0459 AC: 6991 AN: 152280 Hom.: 204 Cov.: 32 AF XY: 0.0485 AC XY: 3609 AN XY: 74462

African (AFR) AF: 0.0549 AC: 2282 AN: 41552

American (AMR) AF: 0.0538 AC: 823 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3470

East Asian (EAS) AF: 0.0814 AC: 422 AN: 5184

South Asian (SAS) AF: 0.0812 AC: 392 AN: 4828

European-Finnish (FIN) AF: 0.0458 AC: 485 AN: 10598

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2207 AN: 68032

Other (OTH) AF: 0.0454 AC: 96 AN: 2114

Alfa AF: 0.0386 Hom.: 145

Bravo AF: 0.0454

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.19
DANN	Benign	0.32
PhyloP100		-1.2

Splicing

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

Other links and lift over

dbSNP: rs16865373; hg19: chr3-190046808;