rs145591298

Variant names:

• chr1-42735969-C-G
• rs145591298
• NM_148960.3:c.535G>C
• CLDN19 p.Gly179Arg

Your query was ambiguous. Multiple possible variants found:

• chr1-42735969-C-G
• chr1-42735969-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_148960.3(CLDN19):​c.535G>C​(p.Gly179Arg) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G179S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN19 NM_148960.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.58
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-42735969-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548672.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-42735969-C-G is Pathogenic according to our data. Variant chr1-42735969-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3242162.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148960.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN19	NM_148960.3	MANE Select	c.535G>C	p.Gly179Arg	missense	Exon 4 of 5	NP_683763.2	Q8N6F1-1
	CLDN19	NM_001123395.2		c.535G>C	p.Gly179Arg	missense	Exon 4 of 4	NP_001116867.1	Q8N6F1-2
	CLDN19	NM_001185117.2		c.450G>C	p.Ala150Ala	synonymous	Exon 3 of 3	NP_001172046.1	Q8N6F1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN19	ENST00000296387.6	TSL:2 MANE Select	c.535G>C	p.Gly179Arg	missense	Exon 4 of 5	ENSP00000296387.1	Q8N6F1-1
	CLDN19	ENST00000372539.3	TSL:1	c.535G>C	p.Gly179Arg	missense	Exon 4 of 4	ENSP00000361617.3	Q8N6F1-2
	CLDN19	ENST00000539749.5	TSL:2	c.450G>C	p.Ala150Ala	synonymous	Exon 3 of 3	ENSP00000443229.1	Q8N6F1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Renal hypomagnesemia 5 with ocular involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.97
gMVP		0.96
Mutation Taster		=24/76	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145591298;

hg19: chr1-43201640;