19-47834480-G-T

Variant names:

• chr19-47834480-G-T
• rs752458888
• NM_000554.6:c.37G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000554.6(CRX):​c.37G>T​(p.Val13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRX NM_000554.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• 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, ClinGen
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29541287).

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.37G>T	p.Val13Phe	missense	Exon 2 of 4	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.37G>T	p.Val13Phe	missense	Exon 2 of 4	ENSP00000221996.5	O43186
	CRX	ENST00000556527.1	TSL:1	n.78-1763G>T		intron	N/A
	CRX	ENST00000566686.5	TSL:5	c.37G>T	p.Val13Phe	missense	Exon 2 of 3	ENSP00000457808.2	H3BUU7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	0.63	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.013	D
Sift4G	Benign	0.13	T
Polyphen		0.14	B
Vest4		0.45
MutPred		0.28		Loss of disorder (P = 0.1298)
MVP		0.73
MPC		0.25
ClinPred		0.87	D
GERP RS		3.0
Varity_R		0.36
gMVP		0.78
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs752458888; hg19: chr19-48337737; COSMIC: COSV55760600;