11-67458392-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.673C>T​(p.Arg225*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,438 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CABP4
NM_145200.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -0.384
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]

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 11-67458392-C-T is Pathogenic according to our data. Variant chr11-67458392-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 438047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67458392-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-67458392-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CABP4NM_145200.5 linkuse as main transcriptc.673C>T p.Arg225* stop_gained 5/6 ENST00000325656.7 NP_660201.1 P57796-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CABP4ENST00000325656.7 linkuse as main transcriptc.673C>T p.Arg225* stop_gained 5/61 NM_145200.5 ENSP00000324960.5 P57796-1
CABP4ENST00000438189.6 linkuse as main transcriptc.358C>T p.Arg120* stop_gained 6/71 ENSP00000401555.2 P57796-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
250020
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135130
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1460150
Hom.:
0
Cov.:
31
AF XY:
0.00000689
AC XY:
5
AN XY:
726152
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152288
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJul 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2019- -
Cone-rod synaptic disorder, congenital nonprogressive Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 14, 2018This variant was identified as homozygous -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 15, 2020This sequence change creates a premature translational stop signal (p.Arg225*) in the CABP4 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs531851447, ExAC 0.007%). This variant has been observed in individual(s) with cone-rod synaptic disorder (PMID: 28041643, 28341476, 29525873). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438047). Loss-of-function variants in CABP4 are known to be pathogenic (PMID: 25307992). For these reasons, this variant has been classified as Pathogenic. -
Cone dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.38
Eigen_PC
Benign
0.082
FATHMM_MKL
Benign
0.14
N
Vest4
0.30
GERP RS
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs531851447; hg19: chr11-67225863; COSMIC: COSV57797205; COSMIC: COSV57797205; API