chr1-42733444-A-G

Position:

• chr1-42733444-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148960.3(CLDN19):​c.*1642T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,282 control chromosomes in the GnomAD database, including 3,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3006 hom., cov: 31)
  • Exomes 𝑓: 0.17 (3 hom.)
• Consequence: CLDN19 NM_148960.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-42733444-A-G is Benign according to our data. Variant chr1-42733444-A-G is described in ClinVar as [Benign]. Clinvar id is 297318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN19	NM_148960.3	c.*1642T>C		3_prime_UTR_variant	5/5	ENST00000296387.6	NP_683763.2
CLDN19	NM_001123395.2	c.*2424T>C		3_prime_UTR_variant	4/4		NP_001116867.1
CLDN19	NM_001185117.2	c.*2318T>C		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.*1642T>C		3_prime_UTR_variant	5/5	2	NM_148960.3	ENSP00000296387
CLDN19	ENST00000539749.5	c.*2318T>C		3_prime_UTR_variant	3/3	2		ENSP00000443229

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28777 AN: 151982 Hom.: 3000 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.170 AC: 31 AN: 182 Hom.: 3 Cov.: 0 AF XY: 0.191 AC XY: 26 AN XY: 136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.189 AC: 28805 AN: 152100 Hom.: 3006 Cov.: 31 AF XY: 0.185 AC XY: 13782 AN XY: 74370

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.198

Alfa AF: 0.176 Hom.: 505

Bravo AF: 0.202

Asia WGS AF: 0.172 AC: 595 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	4.3
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56345167; hg19: chr1-43199115;