19-47834465-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM2BP4_ModerateBP6_ModerateBS1

The NM_000554.6(CRX):c.22G>C(p.Gly8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.97

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 -4 ACMG points.

PM1

In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 56 pathogenic changes around while only 17 benign (77%) in NM_000554.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09923017).

BP6

Variant 19-47834465-G-C is Benign according to our data. Variant chr19-47834465-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1041530.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000204 (31/152222) while in subpopulation AFR AF= 0.000746 (31/41530). AF 95% confidence interval is 0.000539. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6 linkuse as main transcript	c.22G>C	p.Gly8Arg	missense_variant	2/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CRX	ENST00000221996.12 linkuse as main transcript	c.22G>C	p.Gly8Arg	missense_variant	2/4	2	NM_000554.6	P1
CRX	ENST00000556527.1 linkuse as main transcript	n.78-1778G>C		intron_variant, non_coding_transcript_variant		1
CRX	ENST00000566686.5 linkuse as main transcript	c.22G>C	p.Gly8Arg	missense_variant	2/3	5
CRX	ENST00000613299.1 linkuse as main transcript	c.22G>C	p.Gly8Arg	missense_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251476

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000204

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000595

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

T;.;T;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.099

T;T;T;T

MetaSVM

Uncertain

0.22

MutationTaster

Benign

0.77

N;N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.65

N;N;N;.

Sift

Benign

0.032

D;T;T;.

Sift4G

Benign

0.38

T;T;T;D

Polyphen

1.0

.;D;D;.

Vest4

0.43, 0.47, 0.86

MutPred

0.25

Gain of MoRF binding (P = 0.0707);Gain of MoRF binding (P = 0.0707);Gain of MoRF binding (P = 0.0707);Gain of MoRF binding (P = 0.0707);

MVP

0.78

MPC

0.37

ClinPred

0.12

GERP RS

4.0

Varity_R

0.11

gMVP

0.52

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