chr22-46364084-G-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_001378328.1(CELSR1):c.8947C>G(p.Pro2983Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,612,324 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.030 ( 244 hom., cov: 33)
Exomes 𝑓: 0.0033 ( 236 hom. )
Consequence
CELSR1
NM_001378328.1 missense
NM_001378328.1 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 1.65
Genes affected
CELSR1 (HGNC:1850): (cadherin EGF LAG seven-pass G-type receptor 1) The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consists of nonclassic-type cadherins; a subpopulation that does not interact with catenins. The flamingo cadherins are located at the plasma membrane and have nine cadherin domains, seven epidermal growth factor-like repeats and two laminin A G-type repeats in their ectodomain. They also have seven transmembrane domains, a characteristic unique to this subfamily. It is postulated that these proteins are receptors involved in contact-mediated communication, with cadherin domains acting as homophilic binding regions and the EGF-like domains involved in cell adhesion and receptor-ligand interactions. This particular member is a developmentally regulated, neural-specific gene which plays an unspecified role in early embryogenesis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0018625557).
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CELSR1 | NM_001378328.1 | c.8947C>G | p.Pro2983Ala | missense_variant | 34/35 | ENST00000674500.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CELSR1 | ENST00000674500.2 | c.8947C>G | p.Pro2983Ala | missense_variant | 34/35 | NM_001378328.1 | A2 | ||
CELSR1 | ENST00000262738.9 | c.8947C>G | p.Pro2983Ala | missense_variant | 34/35 | 1 | P4 | ||
CELSR1 | ENST00000473624.2 | c.700C>G | p.Pro234Ala | missense_variant | 5/5 | 1 | |||
CELSR1 | ENST00000674159.1 | n.2390C>G | non_coding_transcript_exon_variant | 10/11 |
Frequencies
GnomAD3 genomes ? AF: 0.0302 AC: 4589AN: 152204Hom.: 245 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00788 AC: 1956AN: 248082Hom.: 101 AF XY: 0.00577 AC XY: 779AN XY: 134962
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GnomAD4 exome AF: 0.00334 AC: 4872AN: 1460002Hom.: 236 Cov.: 31 AF XY: 0.00291 AC XY: 2110AN XY: 726238
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GnomAD4 genome ? AF: 0.0301 AC: 4587AN: 152322Hom.: 244 Cov.: 33 AF XY: 0.0293 AC XY: 2182AN XY: 74488
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ESP6500AA
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CELSR1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 10, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
P
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at