22-46364070-C-T

Variant names:

• chr22-46364070-C-T
• rs28495011
• NM_001378328.1:c.8961G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378328.1(CELSR1):​c.8961G>A​(p.Pro2987Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,612,320 control chromosomes in the GnomAD database, including 405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (234 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (171 hom.)
• Consequence: CELSR1 NM_001378328.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.54

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-46364070-C-T is Benign according to our data. Variant chr22-46364070-C-T is described in ClinVar as [Benign]. Clinvar id is 782760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.54 with no splicing effect.
• 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 rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8961G>A	p.Pro2987Pro	synonymous_variant	Exon 34 of 35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELSR1	ENST00000674500.2	c.8961G>A	p.Pro2987Pro	synonymous_variant	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8961G>A	p.Pro2987Pro	synonymous_variant	Exon 34 of 35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.714G>A	p.Pro238Pro	synonymous_variant	Exon 5 of 5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2404G>A		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4547 AN: 152198 Hom.: 235 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00802 AC: 1985 AN: 247482 Hom.: 89 AF XY: 0.00577 AC XY: 777 AN XY: 134720

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00575

Gnomad ASJ exome AF: 0.00383

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000578

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00322 AC: 4700 AN: 1460004 Hom.: 171 Cov.: 31 AF XY: 0.00286 AC XY: 2078 AN XY: 726240

Gnomad4 AFR exome AF: 0.0999

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.00475

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.0299 AC: 4556 AN: 152316 Hom.: 234 Cov.: 33 AF XY: 0.0284 AC XY: 2118 AN XY: 74478

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0146 Hom.: 41

Bravo AF: 0.0340

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CELSR1-related disorder Benign:1

Feb 26, 2020

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.14
DANN	Benign	0.67

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: rs28495011; hg19: chr22-46759967;