22-46364189-C-T

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.729

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=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	UniProt
CELSR1	NM_001378328.1	c.8842G>A	p.Gly2948Ser	missense_variant	34/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.8842G>A	p.Gly2948Ser	missense_variant	34/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.8842G>A	p.Gly2948Ser	missense_variant	34/35	1		P4
CELSR1	ENST00000473624.2	c.595G>A	p.Gly199Ser	missense_variant	5/5	1
CELSR1	ENST00000674159.1	n.2285G>A		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32406 AN: 152124 Hom.: 4674 Cov.: 33

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

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.: 33 AF XY: 0.144 AC XY: 104402 AN XY: 726102

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.: 33 AF XY: 0.210 AC XY: 15608 AN XY: 74440

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: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

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Benign	0.72
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.00093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.24
Sift	Benign	0.74	T
Sift4G	Benign	0.62	T
Polyphen		0.0060	B
Vest4		0.019
MPC		0.17
ClinPred		0.0018	T
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

Other links and lift over

dbSNP: rs35364389; hg19: chr22-46760086; COSMIC: COSV53086583;