rs6776378

Variant names:

• chr3-190312737-G-A
• rs6776378
• NM_021101.5:c.388+135C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000295522.4(CLDN1):​c.388+135C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 931,762 control chromosomes in the GnomAD database, including 29,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5415 hom., cov: 33)
  • Exomes 𝑓: 0.25 (24572 hom.)
• Consequence: CLDN1 ENST00000295522.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.232
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-190312737-G-A is Benign according to our data. Variant chr3-190312737-G-A is described in ClinVar as Benign. ClinVar VariationId is 1265460.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295522.4. 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.388+135C>T		intron	N/A	NP_066924.1
	CLDN16	NM_001378492.1		c.-445-2156G>A		intron	N/A	NP_001365421.1
	CLDN16	NM_001378493.1		c.-279+22146G>A		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.388+135C>T		intron	N/A	ENSP00000295522.3
	CLDN1	ENST00000490800.1	TSL:2	n.347+135C>T		intron	N/A
	P3H2-AS1	ENST00000747181.1		n.627-2156G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39800 AN: 151976 Hom.: 5421 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.249 AC: 193752 AN: 779668 Hom.: 24572 AF XY: 0.250 AC XY: 101751 AN XY: 407530

African (AFR) AF: 0.313 AC: 6299 AN: 20112

American (AMR) AF: 0.211 AC: 8043 AN: 38098

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 4957 AN: 19884

East Asian (EAS) AF: 0.174 AC: 6230 AN: 35864

South Asian (SAS) AF: 0.270 AC: 18053 AN: 66844

European-Finnish (FIN) AF: 0.183 AC: 8375 AN: 45656

Middle Eastern (MID) AF: 0.330 AC: 1082 AN: 3282

European-Non Finnish (NFE) AF: 0.256 AC: 131194 AN: 512274

Other (OTH) AF: 0.253 AC: 9519 AN: 37654

GnomAD4 genome AF: 0.262 AC: 39818 AN: 152094 Hom.: 5415 Cov.: 33 AF XY: 0.259 AC XY: 19238 AN XY: 74340

African (AFR) AF: 0.317 AC: 13172 AN: 41488

American (AMR) AF: 0.230 AC: 3510 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 906 AN: 3464

East Asian (EAS) AF: 0.182 AC: 943 AN: 5176

South Asian (SAS) AF: 0.264 AC: 1274 AN: 4820

European-Finnish (FIN) AF: 0.182 AC: 1922 AN: 10580

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17087 AN: 67972

Other (OTH) AF: 0.274 AC: 578 AN: 2108

Alfa AF: 0.262 Hom.: 5671

Bravo AF: 0.267

Asia WGS AF: 0.232 AC: 805 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.69
PhyloP100		0.23
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: rs6776378; hg19: chr3-190030526; COSMIC: COSV55045180;