22-46390418-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378328.1(CELSR1):c.6319A>G(p.Ile2107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,724 control chromosomes in the GnomAD database, including 37,743 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 0.29 (10299 hom., cov: 33)
  • Exomes 𝑓: 0.17 (27444 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6981847E-6).
• BP6: Variant 22-46390418-T-C is Benign according to our data. Variant chr22-46390418-T-C is described in ClinVar as [Benign]. Clinvar id is 1264263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-46390418-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.6319A>G	p.Ile2107Val	missense_variant	17/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.6319A>G	p.Ile2107Val	missense_variant	17/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.6319A>G	p.Ile2107Val	missense_variant	17/35	1		P4
CELSR1	ENST00000674341.1	n.1396A>G		non_coding_transcript_exon_variant	9/19

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44366 AN: 151952 Hom.: 10260 Cov.: 33

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.171 AC: 42395 AN: 248500 Hom.: 5979 AF XY: 0.163 AC XY: 21948 AN XY: 134720

Gnomad AFR exome AF: 0.660

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.174 AC: 253949 AN: 1460654 Hom.: 27444 Cov.: 31 AF XY: 0.171 AC XY: 124418 AN XY: 726580

Gnomad4 AFR exome AF: 0.660

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.0168

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.292 AC: 44450 AN: 152070 Hom.: 10299 Cov.: 33 AF XY: 0.283 AC XY: 21049 AN XY: 74350

Gnomad4 AFR AF: 0.650

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.0182

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.237

Alfa AF: 0.196 Hom.: 6785

Bravo AF: 0.309

TwinsUK AF: 0.170 AC: 629

ALSPAC AF: 0.176 AC: 678

ESP6500AA AF: 0.647 AC: 2851

ESP6500EA AF: 0.160 AC: 1380

ExAC AF: 0.182 AC: 22028

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.174

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CELSR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 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

GeneDx

Jul 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.030
Dann	Benign	0.39
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.57	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.021
Sift	Benign	0.29	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.14
ClinPred		0.0032	T
GERP RS		-2.9
Varity_R		0.075
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs4044210; hg19: chr22-46786315; COSMIC: COSV53088450;