chr1-42739895-G-A

Variant names:

• chr1-42739895-G-A
• rs118203980
• NM_148960.3:c.169C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_148960.3(CLDN19):​c.169C>T​(p.Gln57*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN19 NM_148960.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.03
• Publications: 8 publications found

Genes affected

CLDN19 (HGNC:2040): (claudin 19) The product of this gene belongs to the claudin family. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Defects in this gene are the cause of hypomagnesemia renal with ocular involvement (HOMGO). HOMGO is a progressive renal disease characterized by primary renal magnesium wasting with hypomagnesemia, hypercalciuria and nephrocalcinosis associated with severe ocular abnormalities such as bilateral chorioretinal scars, macular colobomata, significant myopia and nystagmus. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

CLDN19 Gene-Disease associations (from GenCC):

• renal hypomagnesemia 5 with ocular involvement

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-42739895-G-A is Pathogenic according to our data. Variant chr1-42739895-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 548637.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.169C>T	p.Gln57*	stop_gained	Exon 1 of 5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001185117.2	c.169C>T	p.Gln57*	stop_gained	Exon 1 of 3		NP_001172046.1
CLDN19	NM_001123395.2	c.169C>T	p.Gln57*	stop_gained	Exon 1 of 4		NP_001116867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN19	ENST00000296387.6	c.169C>T	p.Gln57*	stop_gained	Exon 1 of 5	2	NM_148960.3	ENSP00000296387.1
CLDN19	ENST00000372539.3	c.169C>T	p.Gln57*	stop_gained	Exon 1 of 4	1		ENSP00000361617.3
CLDN19	ENST00000539749.5	c.169C>T	p.Gln57*	stop_gained	Exon 1 of 3	2		ENSP00000443229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Renal hypomagnesemia 5 with ocular involvement Pathogenic:1

Jul 10, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		5.0
Vest4		0.89
GERP RS		4.8
PromoterAI		0.0093	Neutral
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs118203980; hg19: chr1-43205566;