1-197427714-T-C

Position:

• chr1-197427714-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_201253.3(CRB1):​c.2389T>C​(p.Ser797Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S797S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.303

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Laminin G-like 2 (size 171) in uniprot entity CRUM1_HUMAN there are 98 pathogenic changes around while only 6 benign (94%) in NM_201253.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757
• PP5: Variant 1-197427714-T-C is Pathogenic according to our data. Variant chr1-197427714-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522783.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr1-197427714-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRB1	NM_201253.3	c.2389T>C	p.Ser797Pro	missense_variant	7/12	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.2389T>C	p.Ser797Pro	missense_variant	7/12	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leber congenital amaurosis 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 21, 2024

Variant summary: CRB1 c.2389T>C (p.Ser797Pro) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250476 control chromosomes. c.2389T>C has been reported in the literature in at least one homozygous individual affected with retinal dystrophy (e.g., Ravesh_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30416334). ClinVar contains an entry for this variant (Variation ID: 522783). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.53	D;.;D;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T;.;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	.;M;M;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.2	D;.;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.010	D;.;D;D;D
Sift4G	Uncertain	0.011	D;.;D;D;D
Polyphen		0.88	P;.;P;P;.
Vest4		0.50
MutPred		0.68		.;Gain of methylation at K799 (P = 0.0909);Gain of methylation at K799 (P = 0.0909);.;.;
MVP		0.85
MPC		0.20
ClinPred		0.93	D
GERP RS		-2.3
Varity_R		0.58
gMVP		0.95

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: rs1355198242; hg19: chr1-197396844;