rs6800425

Variant names:

• chr3-190312535-A-G
• rs6800425
• NM_021101.5:c.388+337T>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.388+337T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 152,078 control chromosomes in the GnomAD database, including 32,942 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 0.65 (32942 hom., cov: 32)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.366
• Publications: 6 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.388+337T>C		intron_variant	Intron 2 of 3	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-445-2358A>G		intron_variant	Intron 1 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+21944A>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.388+337T>C		intron_variant	Intron 2 of 3	1	NM_021101.5	ENSP00000295522.3
CLDN1	ENST00000490800.1	n.347+337T>C		intron_variant	Intron 1 of 1	2
P3H2-AS1	ENST00000747181.1	n.627-2358A>G		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98538 AN: 151960 Hom.: 32900 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.633

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

GnomAD4 genome AF: 0.649 AC: 98627 AN: 152078 Hom.: 32942 Cov.: 32 AF XY: 0.645 AC XY: 47978 AN XY: 74346

African (AFR) AF: 0.808 AC: 33531 AN: 41488

American (AMR) AF: 0.607 AC: 9274 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1744 AN: 3472

East Asian (EAS) AF: 0.765 AC: 3941 AN: 5152

South Asian (SAS) AF: 0.543 AC: 2614 AN: 4814

European-Finnish (FIN) AF: 0.554 AC: 5861 AN: 10574

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39525 AN: 67988

Other (OTH) AF: 0.630 AC: 1331 AN: 2112

Alfa AF: 0.598 Hom.: 20007

Bravo AF: 0.661

Asia WGS AF: 0.600 AC: 2084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.6
DANN	Benign	0.74
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs6800425; hg19: chr3-190030324;