chr3-190322667-G-A

Variant names:

• chr3-190322667-G-A
• rs56235513
• NM_001378492.1:c.-279+7608G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378492.1(CLDN16):​c.-279+7608G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 231,914 control chromosomes in the GnomAD database, including 1,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (988 hom., cov: 32)
  • Exomes 𝑓: 0.11 (570 hom.)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.56
• Publications: 1 publications found

Genes affected

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]

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]

CLDN1 Gene-Disease associations (from GenCC):

• neonatal ichthyosis-sclerosing cholangitis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-190322667-G-A is Benign according to our data. Variant chr3-190322667-G-A is described in ClinVar as Benign. ClinVar VariationId is 1267401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_001378492.1	c.-279+7608G>A		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+32076G>A		intron_variant	Intron 1 of 7		NP_001365422.1
CLDN16	XM_047447333.1	c.-170+6G>A		splice_region_variant, intron_variant	Intron 1 of 6		XP_047303289.1
CLDN1	NM_021101.5	c.-461C>T		upstream_gene_variant		ENST00000295522.4	NP_066924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000468220.1	n.121+6G>A		splice_region_variant, intron_variant	Intron 1 of 4	4
CLDN1	ENST00000295522.4	c.-461C>T		upstream_gene_variant		1	NM_021101.5	ENSP00000295522.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15798 AN: 152150 Hom.: 985 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0628

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.107 AC: 8557 AN: 79646 Hom.: 570 Cov.: 0 AF XY: 0.117 AC XY: 4836 AN XY: 41352

African (AFR) AF: 0.105 AC: 62 AN: 590

American (AMR) AF: 0.179 AC: 573 AN: 3206

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 178 AN: 1676

East Asian (EAS) AF: 0.215 AC: 549 AN: 2550

South Asian (SAS) AF: 0.181 AC: 2297 AN: 12692

European-Finnish (FIN) AF: 0.0705 AC: 402 AN: 5704

Middle Eastern (MID) AF: 0.0924 AC: 29 AN: 314

European-Non Finnish (NFE) AF: 0.0839 AC: 4063 AN: 48408

Other (OTH) AF: 0.0897 AC: 404 AN: 4506

GnomAD4 genome AF: 0.104 AC: 15832 AN: 152268 Hom.: 988 Cov.: 32 AF XY: 0.107 AC XY: 7997 AN XY: 74454

African (AFR) AF: 0.114 AC: 4743 AN: 41554

American (AMR) AF: 0.162 AC: 2474 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1158 AN: 5168

South Asian (SAS) AF: 0.177 AC: 852 AN: 4822

European-Finnish (FIN) AF: 0.0628 AC: 667 AN: 10622

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5269 AN: 68008

Other (OTH) AF: 0.126 AC: 266 AN: 2116

Alfa AF: 0.0859 Hom.: 85

Bravo AF: 0.111

Asia WGS AF: 0.198 AC: 687 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.98
DANN	Benign	0.83
PhyloP100		-2.6
PromoterAI		-0.0080	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56235513; hg19: chr3-190040456;