22-46390418-T-C

Variant names:

• chr22-46390418-T-C
• rs4044210
• NM_001378328.1:c.6319A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:3
• Conservation: PhyloP100: -1.85
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• lymphatic malformation 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neural tube defects, susceptibility to

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hydrops fetalis

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 1264263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.6319A>G	p.Ile2107Val	missense_variant	Exon 17 of 35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELSR1	ENST00000674500.2	c.6319A>G	p.Ile2107Val	missense_variant	Exon 17 of 35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.6319A>G	p.Ile2107Val	missense_variant	Exon 17 of 35	1		ENSP00000262738.3
CELSR1	ENST00000674341.1	n.1396A>G		non_coding_transcript_exon_variant	Exon 9 of 19
CELSR1	ENST00000674359.1	c.*425A>G		downstream_gene_variant				ENSP00000501512.1

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

GnomAD2 exomes AF: 0.171 AC: 42395 AN: 248500 AF XY: 0.163

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 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

African (AFR) AF: 0.660 AC: 22079 AN: 33444

American (AMR) AF: 0.108 AC: 4815 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4725 AN: 26118

East Asian (EAS) AF: 0.0168 AC: 668 AN: 39696

South Asian (SAS) AF: 0.139 AC: 11933 AN: 86076

European-Finnish (FIN) AF: 0.117 AC: 6235 AN: 53310

Middle Eastern (MID) AF: 0.163 AC: 938 AN: 5764

European-Non Finnish (NFE) AF: 0.172 AC: 191640 AN: 1111248

Other (OTH) AF: 0.181 AC: 10916 AN: 60350

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

African (AFR) AF: 0.650 AC: 26929 AN: 41460

American (AMR) AF: 0.160 AC: 2445 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 658 AN: 3470

East Asian (EAS) AF: 0.0182 AC: 94 AN: 5178

South Asian (SAS) AF: 0.126 AC: 607 AN: 4820

European-Finnish (FIN) AF: 0.114 AC: 1209 AN: 10584

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11732 AN: 67956

Other (OTH) AF: 0.237 AC: 501 AN: 2116

Alfa AF: 0.209 Hom.: 16643

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 24, 2019

GeneDx

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

Aug 02, 2019

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	0.062
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
PhyloP100		-1.8
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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