NM_000554.6:c.28C>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_000554.6(CRX):c.28C>G(p.His10Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0006 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 5.83

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 -5 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=0.035576344).

BP6

Variant 19-47834471-C-G is Benign according to our data. Variant chr19-47834471-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329693.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr19-47834471-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000578 (88/152260) while in subpopulation AMR AF= 0.00131 (20/15286). AF 95% confidence interval is 0.000866. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRX	NM_000554.6 link	c.28C>G	p.His10Asp	missense_variant	Exon 2 of 4	ENST00000221996.12	NP_000545.1	O43186

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRX	ENST00000221996.12 link	c.28C>G	p.His10Asp	missense_variant	Exon 2 of 4	2	NM_000554.6	ENSP00000221996.5	O43186
CRX	ENST00000556527.1 link	n.78-1772C>G		intron_variant	Intron 1 of 1	1
CRX	ENST00000566686.5 link	c.28C>G	p.His10Asp	missense_variant	Exon 2 of 3	5		ENSP00000457808.2	H3BUU7
CRX	ENST00000613299.1 link	c.28C>G	p.His10Asp	missense_variant	Exon 2 of 3	3		ENSP00000478106.1	A0A087WTS9

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000489

AC:

123

AN:

251478

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000545

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000603

AC:

881

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000601

AC XY:

437

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000674

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000578

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000497

Hom.:

Bravo

AF:

0.000604

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CRX p.His10Asp variant was identified in the literature in individuals with retinitis pigmentosa and bipolar disorder (Sohocki_2001_PMID:11139241; Maaser_2018_PMID_11139241; Jespersgaard_2019_PMID:30718709). The variant was identified in dbSNP (ID: rs139340178) and ClinVar (classified as likely benign by Illumina and Invitae, and as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen and Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet). The variant was identified in control databases in 133 of 282854 chromosomes at a frequency of 0.0004702 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 41 of 35432 chromosomes (freq: 0.001157), Other in 4 of 7228 chromosomes (freq: 0.000553), European (non-Finnish) in 69 of 129186 chromosomes (freq: 0.000534), South Asian in 15 of 30616 chromosomes (freq: 0.00049), African in 3 of 24950 chromosomes (freq: 0.00012) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.His10 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Retinitis pigmentosa

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Leber congenital amaurosis 7

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy

Uncertain:1

Jan 01, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

.;T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.036

T;T;T;T

MetaSVM

Uncertain

-0.047

MutationAssessor

Benign

0.97

.;L;L;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.4

N;N;N;.

REVEL

Uncertain

0.49

Sift

Benign

0.58

T;T;T;.

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.96

.;D;D;.

Vest4

0.57, 0.55, 0.81

MVP

0.88

MPC

0.57

ClinPred

0.075

GERP RS

4.0

Varity_R

0.29

gMVP

0.71

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