rs73071678

Variant names:

• chr1-197429441-C-T
• rs73071678
• NM_201253.3:c.2677-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201253.3(CRB1):​c.2677-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,613,870 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (21 hom.)
• Consequence: CRB1 NM_201253.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001608
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.43
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-197429441-C-T is Benign according to our data. Variant chr1-197429441-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00898 (1367/152168) while in subpopulation AFR AF = 0.0313 (1299/41518). AF 95% confidence interval is 0.0299. There are 28 homozygotes in GnomAd4. There are 655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,AD gene

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.2677-8C>T		splice_region intron	N/A	NP_957705.1
	CRB1	NM_001257965.2		c.2605-8C>T		splice_region intron	N/A	NP_001244894.1
	CRB1	NM_001193640.2		c.2341-8C>T		splice_region intron	N/A	NP_001180569.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRB1	ENST00000367400.8	TSL:1 MANE Select	c.2677-8C>T		splice_region intron	N/A	ENSP00000356370.3
	CRB1	ENST00000638467.1	TSL:1	c.2677-8C>T		splice_region intron	N/A	ENSP00000491102.1
	CRB1	ENST00000367399.6	TSL:1	c.2341-8C>T		splice_region intron	N/A	ENSP00000356369.2

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1365 AN: 152050 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00218 AC: 548 AN: 251358 AF XY: 0.00155

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000962 AC: 1406 AN: 1461702 Hom.: 21 Cov.: 31 AF XY: 0.000825 AC XY: 600 AN XY: 727162

African (AFR) AF: 0.0319 AC: 1069 AN: 33464

American (AMR) AF: 0.00141 AC: 63 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.000121 AC: 135 AN: 1111868

Other (OTH) AF: 0.00187 AC: 113 AN: 60384

GnomAD4 genome AF: 0.00898 AC: 1367 AN: 152168 Hom.: 28 Cov.: 32 AF XY: 0.00880 AC XY: 655 AN XY: 74390

African (AFR) AF: 0.0313 AC: 1299 AN: 41518

American (AMR) AF: 0.00288 AC: 44 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67996

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00482 Hom.: 2

Bravo AF: 0.00992

Asia WGS AF: 0.00173 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Leber congenital amaurosis 8 (2)
-	-	2	Pigmented paravenous retinochoroidal atrophy (2)
-	-	1	Leber congenital amaurosis (1)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 12 (1)
-	-	1	Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.7
DANN	Benign	0.53
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.012
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: rs73071678; hg19: chr1-197398571;