rs62128766

Positions:

• chr19-47834555-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000554.6(CRX):​c.100+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,608,494 control chromosomes in the GnomAD database, including 24,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1752 hom., cov: 31)
  • Exomes 𝑓: 0.17 (22896 hom.)
• Consequence: CRX NM_000554.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.233

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-47834555-C-T is Benign according to our data. Variant chr19-47834555-C-T is described in ClinVar as [Benign]. Clinvar id is 99592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRX	NM_000554.6	c.100+12C>T		intron_variant		ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12	c.100+12C>T		intron_variant		2	NM_000554.6	ENSP00000221996.5
CRX	ENST00000556527.1	n.78-1688C>T		intron_variant		1
CRX	ENST00000566686.5	c.100+12C>T		intron_variant		5		ENSP00000457808.2
CRX	ENST00000613299.1	c.100+12C>T		intron_variant		3		ENSP00000478106.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21322 AN: 151962 Hom.: 1752 Cov.: 31

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.143 AC: 35773 AN: 250070 Hom.: 2999 AF XY: 0.149 AC XY: 20138 AN XY: 135166

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.0735

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.173 AC: 251642 AN: 1456414 Hom.: 22896 Cov.: 30 AF XY: 0.173 AC XY: 125555 AN XY: 724796

Gnomad4 AFR exome AF: 0.0817

Gnomad4 AMR exome AF: 0.0765

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.140 AC: 21327 AN: 152080 Hom.: 1752 Cov.: 31 AF XY: 0.140 AC XY: 10373 AN XY: 74342

Gnomad4 AFR AF: 0.0844

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.00175

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.141

Alfa AF: 0.164 Hom.: 605

Bravo AF: 0.131

Asia WGS AF: 0.0680 AC: 239 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cone-rod dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Leber congenital amaurosis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.30

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

Other links and lift over

dbSNP: rs62128766; hg19: chr19-48337812;