rs137853136

Variant names:

• chr1-197442284-G-A
• rs137853136
• NM_201253.3:c.3997G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-197442284-G-A
• chr1-197442284-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3 PP5

The NM_201253.3(CRB1):​c.3997G>A​(p.Glu1333Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CRB1 NM_201253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 6.13
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• retinitis pigmentosa 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000230260 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_201253.3
• 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 pigmented paravenous retinochoroidal atrophy, retinitis pigmentosa 12, nanophthalmia, Leber congenital amaurosis, Leber congenital amaurosis 8, hereditary macular dystrophy, retinitis pigmentosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789
• PP5: Variant 1-197442284-G-A is Pathogenic according to our data. Variant chr1-197442284-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 632096.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	NM_201253.3	MANE Select	c.3997G>A	p.Glu1333Lys	missense	Exon 11 of 12	NP_957705.1	P82279-1
	CRB1	NM_001257965.2		c.3925G>A	p.Glu1309Lys	missense	Exon 14 of 15	NP_001244894.1	F5H0L2
	CRB1	NM_001193640.2		c.3661G>A	p.Glu1221Lys	missense	Exon 9 of 10	NP_001180569.1	P82279-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	ENST00000367400.8	TSL:1 MANE Select	c.3997G>A	p.Glu1333Lys	missense	Exon 11 of 12	ENSP00000356370.3	P82279-1
	CRB1	ENST00000638467.1	TSL:1	c.3997G>A	p.Glu1333Lys	missense	Exon 11 of 11	ENSP00000491102.1	P82279-2
	CRB1	ENST00000367399.6	TSL:1	c.3661G>A	p.Glu1221Lys	missense	Exon 9 of 10	ENSP00000356369.2	P82279-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251414 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000286 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis (1)
-	1	-	not specified (1)
-	1	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa 12;C1868310:Pigmented paravenous retinochoroidal atrophy;C3151202:Leber congenital amaurosis 8 (1)
1	-	-	Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		6.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.75
Sift	Benign	0.036	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.52		Gain of methylation at E1333 (P = 0.0103)
MVP		0.99
MPC		0.24
ClinPred		0.85	D
GERP RS		5.6
PromoterAI		-0.059	Neutral
Varity_R		0.53
gMVP		0.78
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs137853136; hg19: chr1-197411414; COSMIC: COSV66332028;