rs55641411

Positions:

• chr3-190322650-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The XM_047447333.1(CLDN16):​c.-181C>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 0.102 in 250,592 control chromosomes in the GnomAD database, including 1,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1018 hom., cov: 32)
  • Exomes 𝑓: 0.096 (616 hom.)
• Consequence: CLDN16 XM_047447333.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.887

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 3-190322650-C-A is Benign according to our data. Variant chr3-190322650-C-A is described in ClinVar as [Benign]. Clinvar id is 1266716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN16	XM_047447333.1	c.-181C>A		5_prime_UTR_variant	1/7		XP_047303289.1
CLDN16	NM_001378492.1	c.-279+7591C>A		intron_variant			NP_001365421.1
CLDN16	NM_001378493.1	c.-279+32059C>A		intron_variant			NP_001365422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000468220.1	n.110C>A		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16041 AN: 152146 Hom.: 1014 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.0962 AC: 9462 AN: 98328 Hom.: 616 Cov.: 0 AF XY: 0.104 AC XY: 5354 AN XY: 51650

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.0983

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0595

Gnomad4 NFE exome AF: 0.0757

Gnomad4 OTH exome AF: 0.0811

GnomAD4 genome AF: 0.106 AC: 16077 AN: 152264 Hom.: 1018 Cov.: 32 AF XY: 0.109 AC XY: 8103 AN XY: 74440

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.0626

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.126

Alfa AF: 0.0859 Hom.: 84

Bravo AF: 0.113

Asia WGS AF: 0.200 AC: 694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.0
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55641411; hg19: chr3-190040439;