Genetic Variant NM_148960.3:c.*1018G>T (chr1-42734068-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.432

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

renal hypomagnesemia 5 with ocular involvement
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

CLDN19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 65 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLDN19	NM_148960.3	MANE Select	c.*1018G>T	3_prime_UTR	Exon 5 of 5	NP_683763.2	Q8N6F1-1
CLDN19	NM_001185117.2		c.*1694G>T	3_prime_UTR	Exon 3 of 3	NP_001172046.1	Q8N6F1-3
CLDN19	NM_001123395.2		c.*1800G>T	3_prime_UTR	Exon 4 of 4	NP_001116867.1	Q8N6F1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN19	ENST00000296387.6	TSL:2 MANE Select	c.*1018G>T		3_prime_UTR	Exon 5 of 5	ENSP00000296387.1	Q8N6F1-1
	CLDN19	ENST00000539749.5	TSL:2	c.*1694G>T		3_prime_UTR	Exon 3 of 3	ENSP00000443229.1	Q8N6F1-3

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3299

AN:

152072

Hom.:

Cov.:

show subpopulations

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:

AN:

444

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

AN XY:

312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0294

AC:

AN:

306

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0217

AC:

3298

AN:

152190

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1629

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00573

AC:

238

AN:

41528

American (AMR)

AF:

0.0181

AC:

277

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

135

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5162

South Asian (SAS)

AF:

0.0504

AC:

243

AN:

4824

European-Finnish (FIN)

AF:

0.0219

AC:

232

AN:

10592

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0297

AC:

2021

AN:

68002

Other (OTH)

AF:

0.0298

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0246

Hom.:

Bravo

AF:

0.0207

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal hypomagnesemia 5 with ocular involvement (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.3

(source)

DANN

Benign

0.79

PhyloP100

-0.43

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over