rs786205521

Positions:

• chr19-47839341-G-A
• chr19-47839341-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000554.6(CRX):​c.274G>A​(p.Ala92Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRX NM_000554.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.15

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity CRX_HUMAN there are 29 pathogenic changes around while only 2 benign (94%) in NM_000554.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 19-47839341-G-A is Pathogenic according to our data. Variant chr19-47839341-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191106.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr19-47839341-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRX	NM_000554.6	c.274G>A	p.Ala92Thr	missense_variant	4/4	ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12	c.274G>A	p.Ala92Thr	missense_variant	4/4	2	NM_000554.6	ENSP00000221996.5
CRX	ENST00000613299.1	c.122G>A	p.Gly41Asp	missense_variant	3/3	3		ENSP00000478106.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Sep 10, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

-

- -

Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with cone rod dystrophy or retinitis pigmentosa (PMID: 26355662, Invitae). ClinVar contains an entry for this variant (Variation ID: 191106). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 92 of the CRX protein (p.Ala92Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.99	D;D
Vest4		0.85
MutPred		0.52		Gain of phosphorylation at A92 (P = 0.0343);Gain of phosphorylation at A92 (P = 0.0343);
MVP		0.94
MPC		0.47
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.53
gMVP		0.86

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

Other links and lift over

dbSNP: rs786205521; hg19: chr19-48342598;