1-197477799-C-T

Position:

• chr1-197477799-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_201253.3(CRB1):​c.4141C>T​(p.Pro1381Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P1381R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Interaction with EPB41L5 (size 36) in uniprot entity CRUM1_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-197477800-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 973928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3	c.4141C>T	p.Pro1381Ser	missense_variant	12/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.4141C>T	p.Pro1381Ser	missense_variant	12/12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	.;T;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.0	.;.;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.48
MutPred		0.23		.;.;Loss of glycosylation at P1381 (P = 0.0247);.;
MVP		0.98
MPC		0.21
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.55
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1201356843; hg19: chr1-197446929;