rs6809685

Variant names:

• chr3-190314805-A-G
• rs6809685
• NM_021101.5:c.224-1769T>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.224-1769T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,124 control chromosomes in the GnomAD database, including 2,115 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 0.16 (2115 hom., cov: 31)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83
• Publications: 4 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN1	NM_021101.5	c.224-1769T>C		intron_variant	Intron 1 of 3	ENST00000295522.4	NP_066924.1
CLDN16	NM_001378492.1	c.-445-88A>G		intron_variant	Intron 1 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+24214A>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.224-1769T>C		intron_variant	Intron 1 of 3	1	NM_021101.5	ENSP00000295522.3
P3H2-AS1	ENST00000747181.1	n.627-88A>G		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24199 AN: 152006 Hom.: 2113 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.0466

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.159 AC: 24218 AN: 152124 Hom.: 2115 Cov.: 31 AF XY: 0.159 AC XY: 11809 AN XY: 74386

African (AFR) AF: 0.232 AC: 9637 AN: 41474

American (AMR) AF: 0.187 AC: 2860 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 612 AN: 3468

East Asian (EAS) AF: 0.0467 AC: 242 AN: 5186

South Asian (SAS) AF: 0.187 AC: 899 AN: 4816

European-Finnish (FIN) AF: 0.0920 AC: 974 AN: 10592

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8504 AN: 67992

Other (OTH) AF: 0.159 AC: 336 AN: 2108

Alfa AF: 0.143 Hom.: 2741

Bravo AF: 0.169

Asia WGS AF: 0.156 AC: 545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.80
PhyloP100		-1.8
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: rs6809685; hg19: chr3-190032594;