rs3902057

Positions:

• chr1-197421238-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_201253.3(CRB1):​c.1410A>G​(p.Leu470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,614,162 control chromosomes in the GnomAD database, including 788,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L470L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.93 (66922 hom., cov: 33)
  • Exomes 𝑓: 0.99 (721292 hom.)
• Consequence: CRB1 NM_201253.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.34

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-197421238-A-G is Benign according to our data. Variant chr1-197421238-A-G is described in ClinVar as [Benign]. Clinvar id is 166956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRB1	NM_201253.3	c.1410A>G	p.Leu470=	synonymous_variant	6/12	ENST00000367400.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRB1	ENST00000367400.8	c.1410A>G	p.Leu470=	synonymous_variant	6/12	1	NM_201253.3	P1

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141711 AN: 152182 Hom.: 66882 Cov.: 33

Gnomad AFR AF: 0.762

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.950

GnomAD3 exomes AF: 0.982 AC: 246879 AN: 251444 Hom.: 121691 AF XY: 0.987 AC XY: 134106 AN XY: 135892

Gnomad AFR exome AF: 0.757

Gnomad AMR exome AF: 0.988

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.993 AC: 1451059 AN: 1461860 Hom.: 721292 Cov.: 66 AF XY: 0.994 AC XY: 722602 AN XY: 727236

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.985

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.984

GnomAD4 genome AF: 0.931 AC: 141809 AN: 152302 Hom.: 66922 Cov.: 33 AF XY: 0.935 AC XY: 69618 AN XY: 74468

Gnomad4 AFR AF: 0.762

Gnomad4 AMR AF: 0.973

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.950

Alfa AF: 0.982 Hom.: 88020

Bravo AF: 0.921

Asia WGS AF: 0.988 AC: 3436 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 20, 2016

- -

Leber congenital amaurosis Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 16, 2019

- -

Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Leber congenital amaurosis 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinitis pigmentosa 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Pigmented paravenous retinochoroidal atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.27
DANN	Benign	0.36

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: rs3902057; hg19: chr1-197390368;