rs61748442

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

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:8B:5O:1

Conservation

PhyloP100: 5.87

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy 2
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
hereditary macular dystrophy
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 7
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 19-47839492-A-G is Benign according to our data. Variant chr19-47839492-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99605.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000554.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	NM_000554.6	MANE Select	c.425A>G	p.Tyr142Cys	missense	Exon 4 of 4	NP_000545.1	O43186

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	ENST00000221996.12	TSL:2 MANE Select	c.425A>G	p.Tyr142Cys	missense	Exon 4 of 4	ENSP00000221996.5	O43186
	CRX	ENST00000613299.1	TSL:3	c.*147A>G		3_prime_UTR	Exon 3 of 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

GnomAD2 exomes

AF:

0.000547

AC:

137

AN:

250542

AF XY:

0.000583

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 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

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.00154

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000306

AC:

340

AN:

1111954

Other (OTH)

AF:

0.000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000362

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41454

American (AMR)

AF:

0.000720

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000501

AC:

AN:

67906

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000545

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinitis pigmentosa (3)

Cone-rod dystrophy 2 (2)

Leber congenital amaurosis 7 (2)

not provided (3)

Autosomal dominant retinitis pigmentosa (1)

CRX-related disorder (1)

Leber congenital amaurosis 1 (1)

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

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.46

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.6

PhyloP100

5.9

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.85

Sift

Benign

0.16

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.63

MVP

0.97

MPC

0.50

ClinPred

0.077

GERP RS

3.9

Varity_R

0.28

gMVP

0.57

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over