19-47834289-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000554.6(CRX):c.-35-120A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 695,998 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (265 hom., cov: 32)
  • Exomes 𝑓: 0.012 (164 hom.)
• Consequence: CRX NM_000554.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.27

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-47834289-A-G is Benign according to our data. Variant chr19-47834289-A-G is described in ClinVar as [Benign]. Clinvar id is 1231525.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6	c.-35-120A>G		intron_variant		ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRX	ENST00000221996.12	c.-35-120A>G		intron_variant		2	NM_000554.6	P1
CRX	ENST00000556527.1	n.78-1954A>G		intron_variant, non_coding_transcript_variant		1
CRX	ENST00000566686.5	c.-35-120A>G		intron_variant		5
CRX	ENST00000613299.1	c.-35-120A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5456 AN: 152180 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0316

GnomAD4 exome AF: 0.0115 AC: 6271 AN: 543700 Hom.: 164 AF XY: 0.0108 AC XY: 3157 AN XY: 292234

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.00571

Gnomad4 EAS exome AF: 0.0507

Gnomad4 SAS exome AF: 0.0165

Gnomad4 FIN exome AF: 0.00173

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0359 AC: 5471 AN: 152298 Hom.: 265 Cov.: 32 AF XY: 0.0355 AC XY: 2646 AN XY: 74472

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0299

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0287 Hom.: 29

Bravo AF: 0.0407

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.24
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3760817; hg19: chr19-48337546; COSMIC: COSV55759808;