22-46364052-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001378328.1(CELSR1):c.8979C>T(p.Asn2993=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,612,120 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: CELSR1 NM_001378328.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.86

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-46364052-G-A is Benign according to our data. Variant chr22-46364052-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3046159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS2: High AC in GnomAd at 342 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.8979C>T	p.Asn2993=	synonymous_variant	34/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.8979C>T	p.Asn2993=	synonymous_variant	34/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.8979C>T	p.Asn2993=	synonymous_variant	34/35	1		P4
CELSR1	ENST00000473624.2	c.732C>T	p.Asn244=	synonymous_variant	5/5	1
CELSR1	ENST00000674159.1	n.2422C>T		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00258 AC: 635 AN: 245832 Hom.: 3 AF XY: 0.00266 AC XY: 356 AN XY: 134082

Gnomad AFR exome AF: 0.000510

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00143

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00267

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00297 AC: 4331 AN: 1459778 Hom.: 13 Cov.: 31 AF XY: 0.00297 AC XY: 2155 AN XY: 726130

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00658

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00231

Gnomad4 NFE exome AF: 0.00331

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00224 AC: 342 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00204 AC XY: 152 AN XY: 74494

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00193

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CELSR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.26
Dann	Benign	0.76

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: rs141868181; hg19: chr22-46759949;