dbSNP rs118203979: CLDN19:p.Gly20Val (chr1-42740005-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_148960.3(CLDN19):c.59G>T(p.Gly20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,396 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. G20D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CLDN19
NM_148960.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a chain Claudin-19 (size 223) in uniprot entity CLD19_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_148960.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-42740005-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN19	NM_148960.3 link	c.59G>T	p.Gly20Val	missense_variant	Exon 1 of 5	ENST00000296387.6	NP_683763.2	Q8N6F1-1
CLDN19	NM_001185117.2 link	c.59G>T	p.Gly20Val	missense_variant	Exon 1 of 3		NP_001172046.1	Q8N6F1-3
CLDN19	NM_001123395.2 link	c.59G>T	p.Gly20Val	missense_variant	Exon 1 of 4		NP_001116867.1	Q8N6F1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLDN19	ENST00000296387.6 link	c.59G>T	p.Gly20Val	missense_variant	Exon 1 of 5	2	NM_148960.3	ENSP00000296387.1	Q8N6F1-1
CLDN19	ENST00000372539.3 link	c.59G>T	p.Gly20Val	missense_variant	Exon 1 of 4	1		ENSP00000361617.3	Q8N6F1-2
CLDN19	ENST00000539749.5 link	c.59G>T	p.Gly20Val	missense_variant	Exon 1 of 3	2		ENSP00000443229.1	Q8N6F1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1425396

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705954

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.15e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.76

MutPred

0.59

Gain of catalytic residue at G20 (P = 0.0648);Gain of catalytic residue at G20 (P = 0.0648);Gain of catalytic residue at G20 (P = 0.0648);

MVP

0.99

MPC

1.1

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.89

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over