rs10754220

Variant names:

• chr1-197275160-G-A
• rs10754220
• NM_201253.3:c.70+6678G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_201253.3(CRB1):​c.70+6678G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 151,764 control chromosomes in the GnomAD database, including 4,217 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4217 hom., cov: 31)
• Consequence: CRB1 NM_201253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 8 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

LOC124904477 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRB1	NM_201253.3	c.70+6678G>A		intron_variant	Intron 1 of 11	ENST00000367400.8	NP_957705.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRB1	ENST00000367400.8	c.70+6678G>A		intron_variant	Intron 1 of 11	1	NM_201253.3	ENSP00000356370.3

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33840 AN: 151646 Hom.: 4214 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.226

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.223 AC: 33849 AN: 151764 Hom.: 4217 Cov.: 31 AF XY: 0.222 AC XY: 16457 AN XY: 74134

African (AFR) AF: 0.114 AC: 4717 AN: 41396

American (AMR) AF: 0.229 AC: 3487 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3468

East Asian (EAS) AF: 0.152 AC: 780 AN: 5136

South Asian (SAS) AF: 0.248 AC: 1191 AN: 4800

European-Finnish (FIN) AF: 0.279 AC: 2938 AN: 10542

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18728 AN: 67892

Other (OTH) AF: 0.229 AC: 483 AN: 2112

Alfa AF: 0.279 Hom.: 6343

Bravo AF: 0.216

Asia WGS AF: 0.208 AC: 723 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.77
DANN	Benign	0.46
PhyloP100		0.078
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10754220; hg19: chr1-197244290;