chr19-47834289-A-G

Variant names:

• chr19-47834289-A-G
• rs3760817
• NM_000554.6:c.-35-120A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.27
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
CRX	NM_000554.6	c.-35-120A>G		intron_variant	Intron 1 of 3	ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12	c.-35-120A>G		intron_variant	Intron 1 of 3	2	NM_000554.6	ENSP00000221996.5
CRX	ENST00000556527.1	n.78-1954A>G		intron_variant	Intron 1 of 1	1
CRX	ENST00000566686.5	c.-35-120A>G		intron_variant	Intron 1 of 2	5		ENSP00000457808.2
CRX	ENST00000613299.1	c.-35-120A>G		intron_variant	Intron 1 of 2	3		ENSP00000478106.1

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

African (AFR) AF: 0.112 AC: 1757 AN: 15736

American (AMR) AF: 0.0220 AC: 748 AN: 33976

Ashkenazi Jewish (ASJ) AF: 0.00571 AC: 107 AN: 18726

East Asian (EAS) AF: 0.0507 AC: 1617 AN: 31870

South Asian (SAS) AF: 0.0165 AC: 985 AN: 59754

European-Finnish (FIN) AF: 0.00173 AC: 66 AN: 38170

Middle Eastern (MID) AF: 0.0146 AC: 58 AN: 3964

European-Non Finnish (NFE) AF: 0.00146 AC: 455 AN: 311452

Other (OTH) AF: 0.0159 AC: 478 AN: 30052

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

African (AFR) AF: 0.111 AC: 4599 AN: 41540

American (AMR) AF: 0.0226 AC: 346 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0299 AC: 155 AN: 5184

South Asian (SAS) AF: 0.0184 AC: 89 AN: 4828

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68030

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.0484 Hom.: 139

Bravo AF: 0.0407

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.24
DANN	Benign	0.56
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3760817; hg19: chr19-48337546; COSMIC: COSV55759808;