chr22-46364189-C-T

Position:

chr22-46364189-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378328.1(CELSR1):c.8842G>A(p.Gly2948Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,611,808 control chromosomes in the GnomAD database, including 22,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4691 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17940 hom. )

Consequence

CELSR1
NM_001378328.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.729

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:

CELSR1 (HGNC:):

CELSR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.2604756E-4).

BP6

Variant 22-46364189-C-T is Benign according to our data. Variant chr22-46364189-C-T is described in ClinVar as [Benign]. Clinvar id is 1257697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-46364189-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR1	NM_001378328.1 linkuse as main transcript	c.8842G>A	p.Gly2948Ser	missense_variant	34/35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CELSR1	ENST00000674500.2 linkuse as main transcript	c.8842G>A	p.Gly2948Ser	missense_variant	34/35		NM_001378328.1	ENSP00000501367.2	A0A6I8PRU0
CELSR1	ENST00000262738.9 linkuse as main transcript	c.8842G>A	p.Gly2948Ser	missense_variant	34/35	1		ENSP00000262738.3	Q9NYQ6-1
CELSR1	ENST00000473624.2 linkuse as main transcript	c.595G>A	p.Gly199Ser	missense_variant	5/5	1		ENSP00000501353.1	A0A6I8PL36
CELSR1	ENST00000674159.1 linkuse as main transcript	n.2285G>A		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32406

AN:

152124

Hom.:

4674

Cov.:

show subpopulations

Gnomad AFR

AF:

0.401

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0584

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.173

GnomAD3 exomes

AF:

0.138

AC:

33991

AN:

247156

Hom.:

3311

AF XY:

0.133

AC XY:

17837

AN XY:

134436

show subpopulations

Gnomad AFR exome

AF:

0.406

Gnomad AMR exome

AF:

0.0816

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.000494

Gnomad SAS exome

AF:

0.0651

Gnomad FIN exome

AF:

0.190

Gnomad NFE exome

AF:

0.151

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.147

AC:

214383

AN:

1459566

Hom.:

17940

Cov.:

AF XY:

0.144

AC XY:

104402

AN XY:

726102

show subpopulations

Gnomad4 AFR exome

AF:

0.412

Gnomad4 AMR exome

AF:

0.0870

Gnomad4 ASJ exome

AF:

0.110

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0675

Gnomad4 FIN exome

AF:

0.183

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.149

GnomAD4 genome

AF:

0.213

AC:

32471

AN:

152242

Hom.:

4691

Cov.:

AF XY:

0.210

AC XY:

15608

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.401

Gnomad4 AMR

AF:

0.129

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0578

Gnomad4 FIN

AF:

0.194

Gnomad4 NFE

AF:

0.155

Gnomad4 OTH

AF:

0.171

Alfa

AF:

0.161

Hom.:

1843

Bravo

AF:

0.217

TwinsUK

AF:

0.147

AC:

544

ALSPAC

AF:

0.158

AC:

610

ESP6500AA

AF:

0.387

AC:

1704

ESP6500EA

AF:

0.144

AC:

1241

ExAC

AF:

0.142

AC:

17227

Asia WGS

AF:

0.0580

AC:

204

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.148

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CELSR1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.074

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.81

MetaRNN

Benign

0.00093

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.37

REVEL

Benign

0.24

Sift

Benign

0.74

Sift4G

Benign

0.62

Polyphen

0.0060

Vest4

0.019

MPC

0.17

ClinPred

0.0018

GERP RS

-0.079

Varity_R

0.037

gMVP

0.056

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