chr1-197421611-G-A

Variant names:

• chr1-197421611-G-A
• rs752212470
• NM_201253.3:c.1783G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_201253.3(CRB1):​c.1783G>A​(p.Ala595Thr) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A595P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.389
• Publications: 7 publications found

Genes affected

CRB1 (HGNC:2343): (crumbs cell polarity complex component 1) This gene encodes a protein which is similar to the Drosophila crumbs protein and localizes to the inner segment of mammalian photoreceptors. In Drosophila crumbs localizes to the stalk of the fly photoreceptor and may be a component of the molecular scaffold that controls proper development of polarity in the eye. Mutations in this gene are associated with a severe form of retinitis pigmentosa, RP12, and with Leber congenital amaurosis. Alternate splicing results in multiple transcript variants, some protein coding and some non-protein coding.[provided by RefSeq, Apr 2012]

CRB1 Gene-Disease associations (from GenCC):

• hereditary macular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Leber congenital amaurosis 8

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• retinitis pigmentosa 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pigmented paravenous retinochoroidal atrophy

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 168 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -1.2832 (below the threshold of 3.09). Trascript score misZ: 0.62189 (below the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis 8, retinitis pigmentosa 12, pigmented paravenous retinochoroidal atrophy, hereditary macular dystrophy, retinitis pigmentosa, Leber congenital amaurosis, nanophthalmia.
• PP5: Variant 1-197421611-G-A is Pathogenic according to our data. Variant chr1-197421611-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190991.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12599233). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	NM_201253.3	MANE Select	c.1783G>A	p.Ala595Thr	missense	Exon 6 of 12	NP_957705.1
	CRB1	NM_001257965.2		c.1576G>A	p.Ala526Thr	missense	Exon 8 of 15	NP_001244894.1
	CRB1	NM_001193640.2		c.1447G>A	p.Ala483Thr	missense	Exon 4 of 10	NP_001180569.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	ENST00000367400.8	TSL:1 MANE Select	c.1783G>A	p.Ala595Thr	missense	Exon 6 of 12	ENSP00000356370.3
	CRB1	ENST00000638467.1	TSL:1	c.1783G>A	p.Ala595Thr	missense	Exon 6 of 11	ENSP00000491102.1
	CRB1	ENST00000367399.6	TSL:1	c.1447G>A	p.Ala483Thr	missense	Exon 4 of 10	ENSP00000356369.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis 8 (1)
1	-	-	not provided (1)
-	1	-	Retinitis pigmentosa 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.9
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.16	N
PhyloP100		0.39
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.11
Sift	Benign	0.23	T
Sift4G	Benign	1.0	T
Polyphen		0.047	B
Vest4		0.026
MutPred		0.65		Gain of glycosylation at A595 (P = 0.0272)
MVP		0.76
MPC		0.034
ClinPred		0.46	T
GERP RS		1.6
Varity_R		0.031
gMVP		0.63
Mutation Taster		=87/13	disease causing (ClinVar)

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: rs752212470; hg19: chr1-197390741; COSMIC: COSV66331230; COSMIC: COSV66331230;