11-67456191-C-T

Position:

chr11-67456191-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_145200.5(CABP4):c.370C>T(p.Arg124Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

CABP4
NM_145200.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 0.510

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-67456191-C-T is Pathogenic according to our data. Variant chr11-67456191-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1953.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr11-67456191-C-T is described in Lovd as [Pathogenic]. Variant chr11-67456191-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABP4	NM_145200.5 linkuse as main transcript	c.370C>T	p.Arg124Cys	missense_variant	2/6	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.370C>T	p.Arg124Cys	missense_variant	2/6	1	NM_145200.5	ENSP00000324960.5	P57796-1
CABP4	ENST00000438189.6 linkuse as main transcript	c.55C>T	p.Arg19Cys	missense_variant	3/7	1		ENSP00000401555.2	P57796-2
CABP4	ENST00000545777.1 linkuse as main transcript	n.*51C>T		non_coding_transcript_exon_variant	2/4	3		ENSP00000439145.1	F5H3E8
CABP4	ENST00000545777.1 linkuse as main transcript	n.*51C>T		3_prime_UTR_variant	2/4	3		ENSP00000439145.1	F5H3E8

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000180

AC:

AN:

250646

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000320

AC:

468

AN:

1461100

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000210

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 124 of the CABP4 protein (p.Arg124Cys). This variant is present in population databases (rs121917828, gnomAD 0.05%). This missense change has been observed in individual(s) with congenital stationary night blindness (PMID: 16960802). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1953). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CABP4 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23099293, 31589614, 33369259, 34426522, 16960802, 35791102) -

Cone-rod synaptic disorder, congenital nonprogressive

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;D

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.6

.;L

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.70

MVP

0.66

MPC

0.47

ClinPred

0.33

GERP RS

4.2

Varity_R

0.60

gMVP

0.68

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.

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