1-42739895-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_148960.3(CLDN19):​c.169C>A​(p.Gln57Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,614 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. Q57E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLDN19 NM_148960.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 7 ACMG points.

• PM1: In a topological_domain Extracellular (size 52) in uniprot entity CLD19_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) 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 chr1-42739895-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1362.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.169C>A	p.Gln57Lys	missense_variant	Exon 1 of 5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001185117.2	c.169C>A	p.Gln57Lys	missense_variant	Exon 1 of 3		NP_001172046.1
CLDN19	NM_001123395.2	c.169C>A	p.Gln57Lys	missense_variant	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>A	p.Gln57Lys	missense_variant	Exon 1 of 5	2	NM_148960.3	ENSP00000296387.1
CLDN19	ENST00000372539.3	c.169C>A	p.Gln57Lys	missense_variant	Exon 1 of 4	1		ENSP00000361617.3
CLDN19	ENST00000539749.5	c.169C>A	p.Gln57Lys	missense_variant	Exon 1 of 3	2		ENSP00000443229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460614 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726512

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.5	H;H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.62
MutPred		0.78		Gain of ubiquitination at Q57 (P = 0.0198);Gain of ubiquitination at Q57 (P = 0.0198);Gain of ubiquitination at Q57 (P = 0.0198);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.79

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.

Other links and lift over

hg19: chr1-43205566; COSMIC: COSV105895202;