Variant chr19-47834472-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000554.6(CRX):c.29A>G(p.His10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H10D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

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:

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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 56 pathogenic changes around while only 17 benign (77%) in NM_000554.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18963775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6 linkuse as main transcript	c.29A>G	p.His10Arg	missense_variant	2/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CRX	ENST00000221996.12 linkuse as main transcript	c.29A>G	p.His10Arg	missense_variant	2/4	2	NM_000554.6	P1
CRX	ENST00000556527.1 linkuse as main transcript	n.78-1771A>G		intron_variant, non_coding_transcript_variant		1
CRX	ENST00000566686.5 linkuse as main transcript	c.29A>G	p.His10Arg	missense_variant	2/3	5
CRX	ENST00000613299.1 linkuse as main transcript	c.29A>G	p.His10Arg	missense_variant	2/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251482

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Usher syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Goettingen

Jun 05, 2020

The CRX variant c.29A>G occurs at a frequency of 0.0008% (gnomAD). The mutation is independently classified as disease causing mutation by three prediction programs. Thus, we consider this variant to be variant of uncertain significance. ACMG criteria used for classification: PM2, PP2, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.22

.;T;T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.70

T;.;T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.28

.;N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.4

N;N;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.32

T;T;T;.

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.14

.;B;B;.

Vest4

0.33, 0.28, 0.42

MutPred

0.30

Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);

MVP

0.77

MPC

0.24

ClinPred

0.17

GERP RS

3.0

Varity_R

0.21

gMVP

0.61

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