chr3-190387914-G-T

Variant names:

• chr3-190387914-G-T
• rs1718545875
• NM_001378492.1:c.-93-323G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378492.1(CLDN16):​c.-93-323G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000449 in 445,404 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.634
• Publications: 0 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ENSG00000297357 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	NM_001378492.1		c.-93-323G>T		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.-93-323G>T		intron	N/A	NP_001365422.1	Q9Y5I7
	CLDN16	NM_006580.4	MANE Select	c.-416G>T		upstream_gene	N/A	NP_006571.2	Q9Y5I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000880223.1		c.-93-323G>T		intron	N/A	ENSP00000550282.1
	CLDN16	ENST00000880225.1		c.-93-323G>T		intron	N/A	ENSP00000550284.1
	CLDN16	ENST00000880227.1		c.-93-323G>T		intron	N/A	ENSP00000550286.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000449 AC: 2 AN: 445404 Hom.: 0 Cov.: 3 AF XY: 0.00000423 AC XY: 1 AN XY: 236524

African (AFR) AF: 0.00 AC: 0 AN: 12404

American (AMR) AF: 0.00 AC: 0 AN: 19558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13442

East Asian (EAS) AF: 0.00 AC: 0 AN: 30388

South Asian (SAS) AF: 0.00 AC: 0 AN: 46270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1926

European-Non Finnish (NFE) AF: 0.00000748 AC: 2 AN: 267344

Other (OTH) AF: 0.00 AC: 0 AN: 25672

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary hypomagnesemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		0.63
PromoterAI		-0.017	Neutral

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

Other links and lift over

dbSNP: rs1718545875; hg19: chr3-190105703;