1-42739895-G-C

Position:

• chr1-42739895-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_148960.3(CLDN19):​c.169C>G​(p.Gln57Glu) variant causes a missense 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).

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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Claudin-19 (size 223) in uniprot entity CLD19_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_148960.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 1-42739895-G-C is Pathogenic according to our data. Variant chr1-42739895-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1362.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.169C>G	p.Gln57Glu	missense_variant	1/5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001185117.2	c.169C>G	p.Gln57Glu	missense_variant	1/3		NP_001172046.1
CLDN19	NM_001123395.2	c.169C>G	p.Gln57Glu	missense_variant	1/4		NP_001116867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN19	ENST00000296387.6	c.169C>G	p.Gln57Glu	missense_variant	1/5	2	NM_148960.3	ENSP00000296387.1
CLDN19	ENST00000372539.3	c.169C>G	p.Gln57Glu	missense_variant	1/4	1		ENSP00000361617.3
CLDN19	ENST00000539749.5	c.169C>G	p.Gln57Glu	missense_variant	1/3	2		ENSP00000443229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Renal hypomagnesemia 5 with ocular involvement Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.81
MutPred		0.76		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.98
MPC		1.0
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.76

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: rs118203980; hg19: chr1-43205566;