chr19-47834451-C-A

Variant names:

• chr19-47834451-C-A
• NM_000554.6:c.8C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000554.6(CRX):​c.8C>A​(p.Ala3Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRX NM_000554.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 37 pathogenic changes around while only 5 benign (88%) in NM_000554.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRX	NM_000554.6	c.8C>A	p.Ala3Glu	missense_variant	Exon 2 of 4	ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12	c.8C>A	p.Ala3Glu	missense_variant	Exon 2 of 4	2	NM_000554.6	ENSP00000221996.5
CRX	ENST00000556527.1	n.78-1792C>A		intron_variant	Intron 1 of 1	1
CRX	ENST00000566686.5	c.8C>A	p.Ala3Glu	missense_variant	Exon 2 of 3	5		ENSP00000457808.2
CRX	ENST00000613299.1	c.8C>A	p.Ala3Glu	missense_variant	Exon 2 of 3	3		ENSP00000478106.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461504 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;.;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.1	.;L;L;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.4	N;N;N;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.92	.;P;P;.
Vest4		0.33, 0.39, 0.55
MutPred		0.18		Loss of catalytic residue at Y4 (P = 0.096);Loss of catalytic residue at Y4 (P = 0.096);Loss of catalytic residue at Y4 (P = 0.096);Loss of catalytic residue at Y4 (P = 0.096);
MVP		0.67
MPC		0.52
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.50
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-48337708;