19-47834486-G-C

Position:

chr19-47834486-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000554.6(CRX):c.43G>C(p.Ala15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.94

Variant links:

Genes affected

CRX (HGNC:2383): (cone-rod homeobox) The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

CRX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 37 pathogenic changes around while only 5 benign (88%) in NM_000554.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22777924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRX	NM_000554.6 linkuse as main transcript	c.43G>C	p.Ala15Pro	missense_variant	2/4	ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CRX	ENST00000221996.12 linkuse as main transcript	c.43G>C	p.Ala15Pro	missense_variant	2/4	2	NM_000554.6	ENSP00000221996	P1
CRX	ENST00000556527.1 linkuse as main transcript	n.78-1757G>C		intron_variant, non_coding_transcript_variant		1
CRX	ENST00000566686.5 linkuse as main transcript	c.43G>C	p.Ala15Pro	missense_variant	2/3	5		ENSP00000457808
CRX	ENST00000613299.1 linkuse as main transcript	c.43G>C	p.Ala15Pro	missense_variant	2/3	3		ENSP00000478106

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt CRX protein function. ClinVar contains an entry for this variant (Variation ID: 867204). This variant has not been reported in the literature in individuals affected with CRX-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 15 of the CRX protein (p.Ala15Pro). -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

.;T;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

D;.;D;D

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.34

.;N;N;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;N;N;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.0030

D;D;D;.

Sift4G

Benign

0.072

T;D;D;T

Polyphen

0.61

.;P;P;.

Vest4

0.28, 0.33, 0.68

MutPred

0.35

Gain of disorder (P = 0.0297);Gain of disorder (P = 0.0297);Gain of disorder (P = 0.0297);Gain of disorder (P = 0.0297);

MVP

0.63

MPC

0.23

ClinPred

0.46

GERP RS

-0.93

Varity_R

0.19

gMVP

0.72

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