22-46364043-G-C

Position:

• chr22-46364043-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001378328.1(CELSR1):​c.8988C>G​(p.Ala2996Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,611,740 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: CELSR1 NM_001378328.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.51

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 22-46364043-G-C is Benign according to our data. Variant chr22-46364043-G-C is described in ClinVar as [Benign]. Clinvar id is 720966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00821 (1251/152296) while in subpopulation AFR AF= 0.0277 (1151/41558). AF 95% confidence interval is 0.0264. There are 18 homozygotes in gnomad4. There are 591 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1251 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8988C>G	p.Ala2996Ala	synonymous_variant	34/35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELSR1	ENST00000674500.2	c.8988C>G	p.Ala2996Ala	synonymous_variant	34/35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8988C>G	p.Ala2996Ala	synonymous_variant	34/35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.741C>G	p.Ala247Ala	synonymous_variant	5/5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2431C>G		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1252 AN: 152178 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00294 AC: 721 AN: 245134 Hom.: 10 AF XY: 0.00265 AC XY: 354 AN XY: 133760

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00635

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00128 AC: 1867 AN: 1459444 Hom.: 38 Cov.: 31 AF XY: 0.00133 AC XY: 968 AN XY: 725944

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00675

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00821 AC: 1251 AN: 152296 Hom.: 18 Cov.: 33 AF XY: 0.00794 AC XY: 591 AN XY: 74462

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00238 Hom.: 1

Bravo AF: 0.00904

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CELSR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

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	-0.44
CADD	Benign	8.9
DANN	Benign	0.81

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: rs77489567; hg19: chr22-46759940;