rs61748438

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000554.6(CRX):c.196G>A(p.Val66Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00345 in 1,614,198 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V66F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 20 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 4.92

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000554.6

BP4

Computational evidence support a benign effect (MetaRNN=0.014583826).

BP6

Variant 19-47836338-G-A is Benign according to our data. Variant chr19-47836338-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-47836338-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0023 (351/152312) while in subpopulation SAS AF= 0.00518 (25/4830). AF 95% confidence interval is 0.0036. There are 4 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6 linkuse as main transcript	c.196G>A	p.Val66Ile	missense_variant	3/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CRX	ENST00000221996.12 linkuse as main transcript	c.196G>A	p.Val66Ile	missense_variant	3/4	2	NM_000554.6	P1
CRX	ENST00000613299.1 linkuse as main transcript	c.100+1795G>A		intron_variant		3
CRX	ENST00000556527.1 linkuse as main transcript			downstream_gene_variant		1
CRX	ENST00000566686.5 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

352

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00324

AC:

815

AN:

251470

Hom.:

AF XY:

0.00343

AC XY:

466

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00879

Gnomad FIN exome

AF:

0.00869

Gnomad NFE exome

AF:

0.00278

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00357

AC:

5226

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

2707

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00777

Gnomad4 FIN exome

AF:

0.00855

Gnomad4 NFE exome

AF:

0.00348

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.00230

AC:

351

AN:

152312

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

194

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00998

Gnomad4 NFE

AF:

0.00288

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00154

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00295

AC:

358

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 27013732, 27884173, 16123401, 24066033, 24265693) -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CRX: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 25, 2016

- -

Leber congenital amaurosis 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cone-rod dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Leber congenital amaurosis 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.11

Cadd

Benign

Dann

Benign

0.28

DEOGEN2

Uncertain

0.53

D;D

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.66

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

-0.045

N;N

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.81

N;N

REVEL

Uncertain

0.56

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.033

B;B

Vest4

0.28

MVP

0.97

MPC

0.15

ClinPred

0.017

GERP RS

2.2

Varity_R

0.060

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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