rs9866788

Variant names:

• chr3-190315331-T-C
• rs9866788
• NM_021101.5:c.224-2295A>G

Variant summary

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

The NM_021101.5(CLDN1):​c.224-2295A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 151,938 control chromosomes in the GnomAD database, including 12,513 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 0.39 (12513 hom., cov: 31)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.457
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.224-2295A>G		intron_variant	Intron 1 of 3	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-279+272T>C		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+24740T>C		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.224-2295A>G		intron_variant	Intron 1 of 3	1	NM_021101.5	ENSP00000295522.3
P3H2-AS1	ENST00000747181.1	n.793+272T>C		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59089 AN: 151818 Hom.: 12514 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.414

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

GnomAD4 genome AF: 0.389 AC: 59098 AN: 151938 Hom.: 12513 Cov.: 31 AF XY: 0.385 AC XY: 28564 AN XY: 74272

African (AFR) AF: 0.233 AC: 9660 AN: 41440

American (AMR) AF: 0.373 AC: 5703 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1598 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1070 AN: 5154

South Asian (SAS) AF: 0.371 AC: 1784 AN: 4810

European-Finnish (FIN) AF: 0.430 AC: 4541 AN: 10572

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33205 AN: 67908

Other (OTH) AF: 0.409 AC: 862 AN: 2110

Alfa AF: 0.397 Hom.: 7608

Bravo AF: 0.379

Asia WGS AF: 0.269 AC: 937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.32
PhyloP100		0.46
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: rs9866788; hg19: chr3-190033120;