rs55641411

Variant names:

• chr3-190322650-C-A
• rs55641411
• ENST00000880223.1:c.-290C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378492.1(CLDN16):​c.-279+7591C>A variant causes a intron 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 NM_001378492.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.887
• 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]

CLDN1 (HGNC:2032): (claudin 1) 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. Loss of function mutations result in neonatal ichthyosis-sclerosing cholangitis syndrome. [provided by RefSeq, Jul 2008]

CLDN1 Gene-Disease associations (from GenCC):

• neonatal ichthyosis-sclerosing cholangitis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.-279+7591C>A		intron	N/A	NP_001365421.1	Q9Y5I7
	CLDN16	NM_001378493.1		c.-279+32059C>A		intron	N/A	NP_001365422.1	Q9Y5I7
	CLDN1	NM_021101.5	MANE Select	c.-444G>T		upstream_gene	N/A	NP_066924.1	O95832

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000880223.1		c.-290C>A		5_prime_UTR	Exon 1 of 8	ENSP00000550282.1
	CLDN16	ENST00000880225.1		c.-313C>A		5_prime_UTR	Exon 1 of 8	ENSP00000550284.1
	CLDN16	ENST00000880227.1		c.-105C>A		5_prime_UTR	Exon 1 of 6	ENSP00000550286.1

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

African (AFR) AF: 0.108 AC: 89 AN: 824

American (AMR) AF: 0.172 AC: 610 AN: 3550

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 208 AN: 2116

East Asian (EAS) AF: 0.197 AC: 613 AN: 3106

South Asian (SAS) AF: 0.156 AC: 2521 AN: 16132

European-Finnish (FIN) AF: 0.0595 AC: 411 AN: 6908

Middle Eastern (MID) AF: 0.102 AC: 39 AN: 384

European-Non Finnish (NFE) AF: 0.0757 AC: 4529 AN: 59856

Other (OTH) AF: 0.0811 AC: 442 AN: 5452

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

African (AFR) AF: 0.120 AC: 4979 AN: 41566

American (AMR) AF: 0.162 AC: 2476 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3468

East Asian (EAS) AF: 0.226 AC: 1166 AN: 5164

South Asian (SAS) AF: 0.177 AC: 851 AN: 4818

European-Finnish (FIN) AF: 0.0626 AC: 665 AN: 10622

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5270 AN: 68014

Other (OTH) AF: 0.126 AC: 267 AN: 2116

Alfa AF: 0.0871 Hom.: 88

Bravo AF: 0.113

Asia WGS AF: 0.200 AC: 694 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.0
DANN	Benign	0.66
PhyloP100		-0.89
PromoterAI		0.0062	Neutral

Splicing

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

Other links and lift over

dbSNP: rs55641411; hg19: chr3-190040439;