22-46364140-G-A

Position:

• chr22-46364140-G-A

Variant summary

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

The NM_001378328.1(CELSR1):​c.8891C>T​(p.Ser2964Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,607,994 control chromosomes in the GnomAD database, including 280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (139 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (141 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.05

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025863945).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8891C>T	p.Ser2964Leu	missense_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.8891C>T	p.Ser2964Leu	missense_variant	34/35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8891C>T	p.Ser2964Leu	missense_variant	34/35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.644C>T	p.Ser215Leu	missense_variant	5/5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2334C>T		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3603 AN: 150012 Hom.: 139 Cov.: 33

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00848

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0174

GnomAD3 exomes AF: 0.00594 AC: 1477 AN: 248558 Hom.: 63 AF XY: 0.00406 AC XY: 548 AN XY: 135070

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00244 AC: 3553 AN: 1457866 Hom.: 141 Cov.: 31 AF XY: 0.00209 AC XY: 1514 AN XY: 725432

Gnomad4 AFR exome AF: 0.0921

Gnomad4 AMR exome AF: 0.00384

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.0240 AC: 3608 AN: 150128 Hom.: 139 Cov.: 33 AF XY: 0.0228 AC XY: 1677 AN XY: 73440

Gnomad4 AFR AF: 0.0867

Gnomad4 AMR AF: 0.00847

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0172

Alfa AF: 0.00164 Hom.: 7

Bravo AF: 0.0269

ESP6500AA AF: 0.0906 AC: 399

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00737 AC: 888

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2020	This variant is associated with the following publications: (PMID: 22095531) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

CELSR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.24
Sift	Uncertain	0.016	D
Sift4G	Benign	0.57	T
Polyphen		1.0	D
Vest4		0.46
MVP		0.61
MPC		0.48
ClinPred		0.097	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.20

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: rs6008777; hg19: chr22-46760037;