3-190343985-T-A

Variant names:

• chr3-190343985-T-A
• rs3846101
• NM_001378492.1:c.-278-26908T>A

Variant summary

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

The NM_001378492.1(CLDN16):​c.-278-26908T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,914 control chromosomes in the GnomAD database, including 35,382 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 0.67 (35382 hom., cov: 32)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.815
• Publications: 1 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_001378492.1	c.-278-26908T>A		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-278-26908T>A		intron_variant	Intron 1 of 7		NP_001365422.1
CLDN16	XM_047447333.1	c.-170+21324T>A		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+21324T>A		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101240 AN: 151794 Hom.: 35334 Cov.: 32

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.659

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.667 AC: 101346 AN: 151914 Hom.: 35382 Cov.: 32 AF XY: 0.668 AC XY: 49624 AN XY: 74232

African (AFR) AF: 0.861 AC: 35729 AN: 41484

American (AMR) AF: 0.687 AC: 10490 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3468

East Asian (EAS) AF: 0.929 AC: 4815 AN: 5184

South Asian (SAS) AF: 0.618 AC: 2968 AN: 4806

European-Finnish (FIN) AF: 0.552 AC: 5820 AN: 10540

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.551 AC: 37397 AN: 67854

Other (OTH) AF: 0.654 AC: 1378 AN: 2106

Alfa AF: 0.610 Hom.: 3655

Bravo AF: 0.691

Asia WGS AF: 0.798 AC: 2774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.40
DANN	Benign	0.38
PhyloP100		-0.81

Splicing

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

Other links and lift over

dbSNP: rs3846101; hg19: chr3-190061774;