22-46364205-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378328.1(CELSR1):c.8826G>A(p.Thr2942=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,611,192 control chromosomes in the GnomAD database, including 1,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (622 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (587 hom.)
• Consequence: CELSR1 NM_001378328.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.02

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-46364205-C-T is Benign according to our data. Variant chr22-46364205-C-T is described in ClinVar as [Benign]. Clinvar id is 1226210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.8826G>A	p.Thr2942=	synonymous_variant	34/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.8826G>A	p.Thr2942=	synonymous_variant	34/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.8826G>A	p.Thr2942=	synonymous_variant	34/35	1		P4
CELSR1	ENST00000473624.2	c.579G>A	p.Thr193=	synonymous_variant	5/5	1
CELSR1	ENST00000674159.1	n.2269G>A		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7580 AN: 152184 Hom.: 622 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0144 AC: 3547 AN: 245988 Hom.: 274 AF XY: 0.0109 AC XY: 1463 AN XY: 133986

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.00874

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.000937

Gnomad SAS exome AF: 0.00301

Gnomad FIN exome AF: 0.000809

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00812

GnomAD4 exome AF: 0.00627 AC: 9150 AN: 1458890 Hom.: 587 Cov.: 32 AF XY: 0.00561 AC XY: 4069 AN XY: 725886

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00275

Gnomad4 FIN exome AF: 0.000974

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0499 AC: 7594 AN: 152302 Hom.: 622 Cov.: 33 AF XY: 0.0475 AC XY: 3540 AN XY: 74464

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0132 Hom.: 58

Bravo AF: 0.0576

Asia WGS AF: 0.0120 AC: 43 AN: 3478

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

Aug 28, 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

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.0060
Dann	Benign	0.62

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: rs6008778; hg19: chr22-46760102;