rs3214506

Positions:

• chr3-190388285-G-A
• chr3-190388285-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006580.4(CLDN16):​c.-45G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: CLDN16 NM_006580.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055850327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN16	NM_006580.4	c.-45G>A		5_prime_UTR_variant	1/5	ENST00000264734.3	NP_006571.2
CLDN16	NM_001378492.1	c.-45G>A		5_prime_UTR_variant	5/9		NP_001365421.1
CLDN16	NM_001378493.1	c.-45G>A		5_prime_UTR_variant	4/8		NP_001365422.1
CLDN16	XM_047447333.1	c.-45G>A		5_prime_UTR_variant	3/7		XP_047303289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN16	ENST00000264734.3	c.-45G>A		5_prime_UTR_variant	1/5	1	NM_006580.4	ENSP00000264734	P1
CLDN16	ENST00000456423.2	c.-45G>A		5_prime_UTR_variant	1/2	1		ENSP00000414136
CLDN16	ENST00000468220.1	n.306+13682G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.6
DANN	Benign	0.84
DEOGEN2	Benign	0.092	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.050	N;N
REVEL	Benign	0.21
Sift	Benign	0.35	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.096
MutPred		0.29		Gain of phosphorylation at A56 (P = 0.0426);Gain of phosphorylation at A56 (P = 0.0426);
MVP		0.60
MPC		0.11
ClinPred		0.20	T
GERP RS		-3.9
Varity_R		0.033
gMVP		0.072

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

Publications

LitVar

Other links and lift over

dbSNP: rs3214506; hg19: chr3-190106074;