11-67457677-C-T

Position:

chr11-67457677-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_145200.5(CABP4):c.646C>T(p.Arg216*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,580,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CABP4
NM_145200.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

CABP4 (HGNC:1386): (calcium binding protein 4) This gene encodes a member of the CABP family of calcium binding protein characterized by four EF-hand motifs. Mutations in this gene are associated with congenital stationary night blindness type 2B. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

CABP4 links:

CABP4 (HGNC:):

CABP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-67457677-C-T is Pathogenic according to our data. Variant chr11-67457677-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67457677-C-T is described in Lovd as [Pathogenic]. Variant chr11-67457677-C-T is described in Lovd as [Pathogenic]. Variant chr11-67457677-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-67457677-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABP4	NM_145200.5 linkuse as main transcript	c.646C>T	p.Arg216*	stop_gained	4/6	ENST00000325656.7	NP_660201.1	P57796-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CABP4	ENST00000325656.7 linkuse as main transcript	c.646C>T	p.Arg216*	stop_gained	4/6	1	NM_145200.5	ENSP00000324960.5	P57796-1
CABP4	ENST00000438189.6 linkuse as main transcript	c.331C>T	p.Arg111*	stop_gained	5/7	1		ENSP00000401555.2	P57796-2
CABP4	ENST00000545777.1 linkuse as main transcript	n.*302C>T		downstream_gene_variant		3		ENSP00000439145.1	F5H3E8

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

193610

Hom.:

AF XY:

0.0000386

AC XY:

AN XY:

103596

show subpopulations

Gnomad AFR exome

AF:

0.0000857

Gnomad AMR exome

AF:

0.0000711

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000799

Gnomad FIN exome

AF:

0.0000609

Gnomad NFE exome

AF:

0.0000479

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

185

AN:

1428700

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

707508

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000508

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000245

Gnomad4 FIN exome

AF:

0.000237

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000668

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	he R216X variant in the CABP4 gene has been reported previously in association with autosomal recessive cone-rod synaptic disorder when present in the homozygous state or when in trans with another disease causing variant (Littink et al., 2009; Smirnov et al., 2018). This variant is predicted to cause loss of normal protein function through protein truncation (Littink et al., 2009). Functional studies demonstrate a damaging effect with reduction in Ca(2+) channel availability and loss of Ca(2+) channel function (Shaltiel et al., 2012). The R216X variant is observed in 2/16,714 (0.012%) alleles from individuals of Finnish European background and in 11/188,328 (0.0058%) global alleles in large population cohorts (Lek et al., 2016). We interpret R216X as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change creates a premature translational stop signal (p.Arg216*) in the CABP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CABP4 are known to be pathogenic (PMID: 25307992). This variant is present in population databases (rs150115958, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinal disease and/or autosomal recessive cone-rod synaptic disorder (PMID: 19074807, 29525873). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190959). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cone-rod synaptic disorder, congenital nonprogressive

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 15, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital nonprogressive cone-rod synaptic disorder (MIM#610427). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). Functional analysis of patient cell-derived RNA suggests NMD-escape, however these results are inconclusive (PMID: 19074807). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants have also been reported in patients with retinal conditions (ClinVar, PMID: 29706639). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and in both homozygous and compound heterozygous patients with cone-rod disorders, retinal diseases and achromatopsia (ClinVar, PMID: 19074807, PMID: 29525873, PMID: 30718709). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001669). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -

Achromatopsia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Cone-rod dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.81

Vest4

0.29

GERP RS

4.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over