chr1-42734068-C-A

Position:

• chr1-42734068-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_148960.3(CLDN19):​c.*1018G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 152,634 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (65 hom., cov: 32)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: CLDN19 NM_148960.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.432

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-42734068-C-A is Benign according to our data. Variant chr1-42734068-C-A is described in ClinVar as [Benign]. Clinvar id is 297325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0217 (3298/152190) while in subpopulation SAS AF= 0.0504 (243/4824). AF 95% confidence interval is 0.0452. There are 65 homozygotes in gnomad4. There are 1629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 65 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.*1018G>T		3_prime_UTR_variant	5/5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001123395.2	c.*1800G>T		3_prime_UTR_variant	4/4		NP_001116867.1
CLDN19	NM_001185117.2	c.*1694G>T		3_prime_UTR_variant	3/3		NP_001172046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN19	ENST00000296387.6	c.*1018G>T		3_prime_UTR_variant	5/5	2	NM_148960.3	ENSP00000296387
CLDN19	ENST00000539749.5	c.*1694G>T		3_prime_UTR_variant	3/3	2		ENSP00000443229

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3299 AN: 152072 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00575

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0203 AC: 9 AN: 444 Hom.: 0 Cov.: 0 AF XY: 0.0160 AC XY: 5 AN XY: 312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0294

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0217 AC: 3298 AN: 152190 Hom.: 65 Cov.: 32 AF XY: 0.0219 AC XY: 1629 AN XY: 74408

Gnomad4 AFR AF: 0.00573

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0504

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0246 Hom.: 8

Bravo AF: 0.0207

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 5 with ocular involvement Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.3
DANN	Benign	0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114944537; hg19: chr1-43199739;