rs61748445

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 12/21 in silico tools predict 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

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: 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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 -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId 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.

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.472G>A	p.Ala158Thr	missense	Exon 4 of 4	NP_000545.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	ENST00000221996.12	TSL:2 MANE Select	c.472G>A	p.Ala158Thr	missense	Exon 4 of 4	ENSP00000221996.5
	CRX	ENST00000613299.1	TSL:3	c.*194G>A		3_prime_UTR	Exon 3 of 3	ENSP00000478106.1

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

GnomAD2 exomes

AF:

0.00689

AC:

1720

AN:

249576

AF XY:

0.00499

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 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

African (AFR)

AF:

0.0902

AC:

3021

AN:

33476

American (AMR)

AF:

0.00620

AC:

277

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00261

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000242

AC:

269

AN:

1111682

Other (OTH)

AF:

0.00583

AC:

352

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

245

489

734

978

1223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.0239

AC:

3636

AN:

152130

Hom.:

151

Cov.:

AF XY:

0.0233

AC XY:

1732

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0817

AC:

3391

AN:

41486

American (AMR)

AF:

0.0110

AC:

168

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67972

Other (OTH)

AF:

0.0166

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

161

322

484

645

806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0115

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Cone-rod dystrophy 2 (1)

Leber congenital amaurosis 7 (1)

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

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Retinitis pigmentosa;C3151192:Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.2

PhyloP100

4.2

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.69

REVEL

Benign

0.27

Sift

Benign

0.18

Sift4G

Benign

0.21

Polyphen

0.012

Vest4

0.40

MVP

0.72

MPC

0.27

ClinPred

0.011

GERP RS

2.0

Varity_R

0.058

gMVP

0.55

Mutation Taster

=88/12

polymorphism (auto)

(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