rs3732924

Variant names:

• chr3-190316818-T-G
• rs3732924
• NM_021101.5:c.224-3782A>C

Variant summary

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

The NM_021101.5(CLDN1):​c.224-3782A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,034 control chromosomes in the GnomAD database, including 6,665 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 0.29 (6665 hom., cov: 32)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 2 publications found

Genes affected

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]

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]

P3H2-AS1 (HGNC:40886): (P3H2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.224-3782A>C		intron_variant	Intron 1 of 3	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-279+1759T>G		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+26227T>G		intron_variant	Intron 1 of 7		NP_001365422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN1	ENST00000295522.4	c.224-3782A>C		intron_variant	Intron 1 of 3	1	NM_021101.5	ENSP00000295522.3
P3H2-AS1	ENST00000747181.1	n.793+1759T>G		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43994 AN: 151916 Hom.: 6670 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.271

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

GnomAD4 genome AF: 0.289 AC: 43990 AN: 152034 Hom.: 6665 Cov.: 32 AF XY: 0.292 AC XY: 21706 AN XY: 74328

African (AFR) AF: 0.256 AC: 10618 AN: 41484

American (AMR) AF: 0.299 AC: 4559 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 858 AN: 3468

East Asian (EAS) AF: 0.569 AC: 2942 AN: 5168

South Asian (SAS) AF: 0.184 AC: 888 AN: 4820

European-Finnish (FIN) AF: 0.341 AC: 3601 AN: 10546

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19469 AN: 67960

Other (OTH) AF: 0.269 AC: 569 AN: 2112

Alfa AF: 0.302 Hom.: 2178

Bravo AF: 0.292

Asia WGS AF: 0.358 AC: 1240 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs3732924; hg19: chr3-190034607;