rs61748442

Positions:

chr19-47839492-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BS1BS2

The NM_000554.6(CRX):c.425A>G(p.Tyr142Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,613,762 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:5O:1

Conservation

PhyloP100: 5.87

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a region_of_interest Disordered (size 62) in uniprot entity CRX_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000554.6

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000362 (55/151980) while in subpopulation AMR AF= 0.00072 (11/15282). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRX	NM_000554.6 linkuse as main transcript	c.425A>G	p.Tyr142Cys	missense_variant	4/4	ENST00000221996.12	NP_000545.1	O43186

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12 linkuse as main transcript	c.425A>G	p.Tyr142Cys	missense_variant	4/4	2	NM_000554.6	ENSP00000221996.5		O43186
CRX	ENST00000613299.1 linkuse as main transcript	c.*147A>G		3_prime_UTR_variant	3/3	3		ENSP00000478106.1		A0A087WTS9

Frequencies

GnomAD3 genomes

AF:

0.000369

AC:

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000501

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000547

AC:

137

AN:

250542

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000539

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.000376

AC:

550

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000306

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000362

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000501

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000694

Hom.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 24265693, 16123401, 27884173, 27668495, 26355662) -

Retinitis pigmentosa

Uncertain:2

Uncertain significance, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Leber congenital amaurosis 7

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal dominant retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Sep 10, 2015

- -

Leber congenital amaurosis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2020

- -

Cone-rod dystrophy 2

Benign:1

Benign, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

CRX-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;D

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.85

Sift

Benign

0.16

T;T

Sift4G

Benign

0.12

T;T

Polyphen

1.0

D;D

Vest4

0.63

MVP

0.97

MPC

0.50

ClinPred

0.077

GERP RS

3.9

Varity_R

0.28

gMVP

0.57

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