22-46364084-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378328.1(CELSR1):c.8947C>G(p.Pro2983Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,612,324 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (244 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (236 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018625557).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.8947C>G	p.Pro2983Ala	missense_variant	34/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.8947C>G	p.Pro2983Ala	missense_variant	34/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.8947C>G	p.Pro2983Ala	missense_variant	34/35	1		P4
CELSR1	ENST00000473624.2	c.700C>G	p.Pro234Ala	missense_variant	5/5	1
CELSR1	ENST00000674159.1	n.2390C>G		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4589 AN: 152204 Hom.: 245 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00788 AC: 1956 AN: 248082 Hom.: 101 AF XY: 0.00577 AC XY: 779 AN XY: 134962

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00334 AC: 4872 AN: 1460002 Hom.: 236 Cov.: 31 AF XY: 0.00291 AC XY: 2110 AN XY: 726238

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.00555

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000495

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.0301 AC: 4587 AN: 152322 Hom.: 244 Cov.: 33 AF XY: 0.0293 AC XY: 2182 AN XY: 74488

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0101 Hom.: 26

Bravo AF: 0.0342

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00980 AC: 1187

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000534

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

Apr 10, 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

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	10
Dann	Benign	0.92
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Benign	0.078	T
Polyphen		0.030	B
Vest4		0.67
MVP		0.50
MPC		0.16
ClinPred		0.013	T
GERP RS		2.3
Varity_R		0.041
gMVP		0.12

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: rs61741871; hg19: chr22-46759981;