chr3-190318025-A-G

Variant names:

• chr3-190318025-A-G
• rs3774024
• NM_021101.5:c.223+3959T>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.223+3959T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0543 in 152,326 control chromosomes in the GnomAD database, including 320 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 0.054 (320 hom., cov: 32)
• Consequence: CLDN1 NM_021101.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021101.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN1	NM_021101.5	MANE Select	c.223+3959T>C		intron	N/A	NP_066924.1
	CLDN16	NM_001378492.1		c.-279+2966A>G		intron	N/A	NP_001365421.1
	CLDN16	NM_001378493.1		c.-279+27434A>G		intron	N/A	NP_001365422.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN1	ENST00000295522.4	TSL:1 MANE Select	c.223+3959T>C		intron	N/A	ENSP00000295522.3
	P3H2-AS1	ENST00000747181.1		n.793+2966A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8257 AN: 152208 Hom.: 318 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0726

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

GnomAD4 genome AF: 0.0543 AC: 8273 AN: 152326 Hom.: 320 Cov.: 32 AF XY: 0.0554 AC XY: 4130 AN XY: 74486

African (AFR) AF: 0.0441 AC: 1833 AN: 41564

American (AMR) AF: 0.106 AC: 1619 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.145 AC: 755 AN: 5190

South Asian (SAS) AF: 0.0957 AC: 462 AN: 4830

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3134 AN: 68030

Other (OTH) AF: 0.0756 AC: 160 AN: 2116

Alfa AF: 0.0524 Hom.: 356

Bravo AF: 0.0610

Asia WGS AF: 0.129 AC: 449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.69
PhyloP100		-0.32
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: rs3774024; hg19: chr3-190035814;