chr1-42733353-C-T

Variant names:

• chr1-42733353-C-T
• rs112310775
• NM_148960.3:c.*1733G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148960.3(CLDN19):​c.*1733G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,564 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1173 hom., cov: 32)
  • Exomes 𝑓: 0.091 (2 hom.)
• Consequence: CLDN19 NM_148960.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.200
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-42733353-C-T is Benign according to our data. Variant chr1-42733353-C-T is described in ClinVar as Benign. ClinVar VariationId is 297316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN19	NM_148960.3	MANE Select	c.*1733G>A		3_prime_UTR	Exon 5 of 5	NP_683763.2	Q8N6F1-1
	CLDN19	NM_001185117.2		c.*2409G>A		3_prime_UTR	Exon 3 of 3	NP_001172046.1	Q8N6F1-3
	CLDN19	NM_001123395.2		c.*2515G>A		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.*1733G>A		3_prime_UTR	Exon 5 of 5	ENSP00000296387.1	Q8N6F1-1
	CLDN19	ENST00000539749.5	TSL:2	c.*2409G>A		3_prime_UTR	Exon 3 of 3	ENSP00000443229.1	Q8N6F1-3

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18520 AN: 152038 Hom.: 1173 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.0684

Gnomad FIN AF: 0.0901

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.0907 AC: 37 AN: 408 Hom.: 2 Cov.: 0 AF XY: 0.0987 AC XY: 31 AN XY: 314

African (AFR) AF: 0.200 AC: 2 AN: 10

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2 AN: 4

East Asian (EAS) AF: 0.0833 AC: 1 AN: 12

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.0893 AC: 30 AN: 336

Other (OTH) AF: 0.0625 AC: 1 AN: 16

GnomAD4 genome AF: 0.122 AC: 18532 AN: 152156 Hom.: 1173 Cov.: 32 AF XY: 0.119 AC XY: 8868 AN XY: 74400

African (AFR) AF: 0.132 AC: 5497 AN: 41488

American (AMR) AF: 0.121 AC: 1844 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1065 AN: 5166

South Asian (SAS) AF: 0.0685 AC: 330 AN: 4820

European-Finnish (FIN) AF: 0.0901 AC: 955 AN: 10598

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7841 AN: 68002

Other (OTH) AF: 0.128 AC: 270 AN: 2106

Alfa AF: 0.125 Hom.: 147

Bravo AF: 0.128

Asia WGS AF: 0.142 AC: 491 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Renal hypomagnesemia 5 with ocular involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.8
DANN	Benign	0.25
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs112310775; hg19: chr1-43199024;