dbSNP rs376054333: CELSR1:p.Arg3000Leu (chr22-46364032-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378328.1(CELSR1):c.8999G>T(p.Arg3000Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CELSR1
NM_001378328.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

Variant links:

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]

CELSR1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12817857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1 link	c.8999G>T	p.Arg3000Leu	missense_variant	Exon 34 of 35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CELSR1	ENST00000674500.2 link	c.8999G>T	p.Arg3000Leu	missense_variant	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2	A0A6I8PRU0
CELSR1	ENST00000262738.9 link	c.8999G>T	p.Arg3000Leu	missense_variant	Exon 34 of 35	1		ENSP00000262738.3	Q9NYQ6-1
CELSR1	ENST00000473624.2 link	c.752G>T	p.Arg251Leu	missense_variant	Exon 5 of 5	1		ENSP00000501353.1	A0A6I8PL36
CELSR1	ENST00000674159.1 link	n.2442G>T		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458718

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725530

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.22

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.66

M_CAP

Benign

0.072

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.3

REVEL

Benign

0.12

Sift

Benign

0.073

Sift4G

Benign

0.16

Polyphen

0.30

Vest4

0.21

MutPred

0.30

Loss of MoRF binding (P = 0.0138);

MVP

0.47

MPC

0.27

ClinPred

0.39

GERP RS

4.8

Varity_R

0.15

gMVP

0.11

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over