chr19-47834259-T-C

Variant names:

• chr19-47834259-T-C
• rs4801737
• NM_000554.6:c.-35-150T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000554.6(CRX):​c.-35-150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 645,826 control chromosomes in the GnomAD database, including 3,829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1948 hom., cov: 31)
  • Exomes 𝑓: 0.067 (1881 hom.)
• Consequence: CRX NM_000554.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.218
• Publications: 2 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: ClinGen, 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-47834259-T-C is Benign according to our data. Variant chr19-47834259-T-C is described in ClinVar as Benign. ClinVar VariationId is 1243300.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000554.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	NM_000554.6	MANE Select	c.-35-150T>C		intron	N/A	NP_000545.1	O43186

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	ENST00000221996.12	TSL:2 MANE Select	c.-35-150T>C		intron	N/A	ENSP00000221996.5	O43186
	CRX	ENST00000556527.1	TSL:1	n.78-1984T>C		intron	N/A
	CRX	ENST00000566686.5	TSL:5	c.-35-150T>C		intron	N/A	ENSP00000457808.2	H3BUU7

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18161 AN: 152064 Hom.: 1939 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0809

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0504

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0673 AC: 33210 AN: 493644 Hom.: 1881 AF XY: 0.0699 AC XY: 18382 AN XY: 262966

African (AFR) AF: 0.289 AC: 4139 AN: 14342

American (AMR) AF: 0.0572 AC: 1697 AN: 29650

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 1981 AN: 16268

East Asian (EAS) AF: 0.000419 AC: 13 AN: 31008

South Asian (SAS) AF: 0.123 AC: 6588 AN: 53568

European-Finnish (FIN) AF: 0.0286 AC: 910 AN: 31810

Middle Eastern (MID) AF: 0.129 AC: 451 AN: 3504

European-Non Finnish (NFE) AF: 0.0527 AC: 15065 AN: 285662

Other (OTH) AF: 0.0850 AC: 2366 AN: 27832

GnomAD4 genome AF: 0.120 AC: 18206 AN: 152182 Hom.: 1948 Cov.: 31 AF XY: 0.119 AC XY: 8838 AN XY: 74414

African (AFR) AF: 0.287 AC: 11928 AN: 41492

American (AMR) AF: 0.0807 AC: 1233 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.134 AC: 646 AN: 4818

European-Finnish (FIN) AF: 0.0251 AC: 267 AN: 10618

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0505 AC: 3431 AN: 68000

Other (OTH) AF: 0.108 AC: 228 AN: 2110

Alfa AF: 0.0613 Hom.: 710

Bravo AF: 0.132

Asia WGS AF: 0.0910 AC: 318 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.3
DANN	Benign	0.57
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs4801737; hg19: chr19-48337516;