22-46364140-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001378328.1(CELSR1):c.8891C>T(p.Ser2964Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,607,994 control chromosomes in the GnomAD database, including 280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 139 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 141 hom. )

Consequence

CELSR1
NM_001378328.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025863945).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1 link	c.8891C>T	p.Ser2964Leu	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.8891C>T	p.Ser2964Leu	missense_variant	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2	A0A6I8PRU0
CELSR1	ENST00000262738.9 link	c.8891C>T	p.Ser2964Leu	missense_variant	Exon 34 of 35	1		ENSP00000262738.3	Q9NYQ6-1
CELSR1	ENST00000473624.2 link	c.644C>T	p.Ser215Leu	missense_variant	Exon 5 of 5	1		ENSP00000501353.1	A0A6I8PL36
CELSR1	ENST00000674159.1 link	n.2334C>T		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3603

AN:

150012

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00848

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0174

GnomAD3 exomes

AF:

0.00594

AC:

1477

AN:

248558

Hom.:

AF XY:

0.00406

AC XY:

548

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.0841

Gnomad AMR exome

AF:

0.00299

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.00244

AC:

3553

AN:

1457866

Hom.:

141

Cov.:

AF XY:

0.00209

AC XY:

1514

AN XY:

725432

show subpopulations

Gnomad4 AFR exome

AF:

0.0921

Gnomad4 AMR exome

AF:

0.00384

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.0000810

Gnomad4 OTH exome

AF:

0.00542

GnomAD4 genome

AF:

0.0240

AC:

3608

AN:

150128

Hom.:

139

Cov.:

AF XY:

0.0228

AC XY:

1677

AN XY:

73440

show subpopulations

Gnomad4 AFR

AF:

0.0867

Gnomad4 AMR

AF:

0.00847

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.0172

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.0269

ESP6500AA

AF:

0.0906

AC:

399

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00737

AC:

888

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 21, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22095531) -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CELSR1-related disorder

Benign:1

Jan 03, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

0.18

Eigen_PC

Benign

0.068

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.4

REVEL

Benign

0.24

Sift

Uncertain

0.016

Sift4G

Benign

0.57

Polyphen

1.0

Vest4

0.46

MVP

0.61

MPC

0.48

ClinPred

0.097

GERP RS

4.8

Varity_R

0.15

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over