NM_000554.6:c.472G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000554.6(CRX):c.472G>A(p.Ala158Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00475 in 1,613,370 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 151 hom., cov: 31)

Exomes 𝑓: 0.0028 ( 144 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 4.24

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 Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0023398101).

BP6

Variant 19-47839539-G-A is Benign according to our data. Variant chr19-47839539-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRX	NM_000554.6 link	c.472G>A	p.Ala158Thr	missense_variant	Exon 4 of 4	ENST00000221996.12	NP_000545.1	O43186

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12 link	c.472G>A	p.Ala158Thr	missense_variant	Exon 4 of 4	2	NM_000554.6	ENSP00000221996.5		O43186
CRX	ENST00000613299.1 link	c.*194G>A		3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000478106.1		A0A087WTS9

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3628

AN:

152012

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0818

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0168

GnomAD3 exomes

AF:

0.00689

AC:

1720

AN:

249576

Hom.:

AF XY:

0.00499

AC XY:

674

AN XY:

135118

show subpopulations

Gnomad AFR exome

AF:

0.0901

Gnomad AMR exome

AF:

0.00542

Gnomad ASJ exome

AF:

0.00231

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000311

Gnomad OTH exome

AF:

0.00477

GnomAD4 exome

AF:

0.00276

AC:

4033

AN:

1461240

Hom.:

144

Cov.:

AF XY:

0.00241

AC XY:

1751

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.0902

Gnomad4 AMR exome

AF:

0.00620

Gnomad4 ASJ exome

AF:

0.00261

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000242

Gnomad4 OTH exome

AF:

0.00583

GnomAD4 genome

AF:

0.0239

AC:

3636

AN:

152130

Hom.:

151

Cov.:

AF XY:

0.0233

AC XY:

1732

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0817

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.0280

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0908

AC:

400

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00821

AC:

996

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10766140, 20981092) -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Sep 15, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa;C3151192:Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2

Benign:1

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 7

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy

Benign:1

Jan 01, 2012

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.88

.;D

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.69

N;N

REVEL

Benign

0.27

Sift

Benign

0.18

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.012

B;B

Vest4

0.40

MVP

0.72

MPC

0.27

ClinPred

0.011

GERP RS

2.0

Varity_R

0.058

gMVP

0.55

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