NM_001378492.1:c.-279+14941G>A

Variant names:

• chr3-190330000-G-A
• rs16865380
• NM_001378492.1:c.-279+14941G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378492.1(CLDN16):​c.-279+14941G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 151,900 control chromosomes in the GnomAD database, including 318 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 0.043 (318 hom., cov: 32)
• Consequence: CLDN16 NM_001378492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397
• 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]

CLDN16 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

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 = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN16	NM_001378492.1	c.-279+14941G>A		intron_variant	Intron 2 of 8		NP_001365421.1
CLDN16	NM_001378493.1	c.-279+39409G>A		intron_variant	Intron 1 of 7		NP_001365422.1
CLDN16	XM_047447333.1	c.-170+7339G>A		intron_variant	Intron 1 of 6		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000468220.1	n.121+7339G>A		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6469 AN: 151782 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.00607

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.0253

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

GnomAD4 genome AF: 0.0427 AC: 6479 AN: 151900 Hom.: 318 Cov.: 32 AF XY: 0.0426 AC XY: 3166 AN XY: 74242

African (AFR) AF: 0.119 AC: 4908 AN: 41370

American (AMR) AF: 0.0194 AC: 296 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00607 AC: 21 AN: 3462

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5166

South Asian (SAS) AF: 0.0898 AC: 431 AN: 4802

European-Finnish (FIN) AF: 0.0158 AC: 167 AN: 10576

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00867 AC: 589 AN: 67940

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0253 Hom.: 72

Bravo AF: 0.0442

Asia WGS AF: 0.0580 AC: 204 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	1.5
DANN	Benign	0.66
PhyloP100		0.40

Splicing

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

Other links and lift over

dbSNP: rs16865380; hg19: chr3-190047789;