rs765256758

Variant names:

• chr3-190402428-C-A
• rs765256758
• NM_006580.4:c.206C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-190402428-C-A
• chr3-190402428-C-G
• chr3-190402428-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_006580.4(CLDN16):​c.206C>A​(p.Ala69Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A69V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLDN16 NM_006580.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 54) in uniprot entity CLD16_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_006580.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-190402428-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545702.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.076836 (below the threshold of 3.09). Trascript score misZ: 0.28069 (below the threshold of 3.09). GenCC associations: The gene is linked to renal hypomagnesemia 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006580.4. 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
	CLDN16	NM_006580.4	MANE Select	c.206C>A	p.Ala69Glu	missense	Exon 2 of 5	NP_006571.2
	CLDN16	NM_001378492.1		c.206C>A	p.Ala69Glu	missense	Exon 6 of 9	NP_001365421.1
	CLDN16	NM_001378493.1		c.206C>A	p.Ala69Glu	missense	Exon 5 of 8	NP_001365422.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN16	ENST00000264734.3	TSL:1 MANE Select	c.206C>A	p.Ala69Glu	missense	Exon 2 of 5	ENSP00000264734.3
	CLDN16	ENST00000456423.2	TSL:1	c.115-7475C>A		intron	N/A	ENSP00000414136.2
	CLDN16	ENST00000468220.1	TSL:4	n.398C>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460322 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726610

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110606

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.59		Gain of solvent accessibility (P = 0.005)
MVP		0.96
MPC		0.31
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.72
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs765256758; hg19: chr3-190120217; COSMIC: COSV53228629;