22-46364206-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001378328.1(CELSR1):c.8825C>T(p.Thr2942Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,610,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T2942T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13676274).
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.8825C>T	p.Thr2942Met	missense_variant	34/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.8825C>T	p.Thr2942Met	missense_variant	34/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.8825C>T	p.Thr2942Met	missense_variant	34/35	1		P4
CELSR1	ENST00000473624.2	c.578C>T	p.Thr193Met	missense_variant	5/5	1
CELSR1	ENST00000674159.1	n.2268C>T		non_coding_transcript_exon_variant	10/11

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000691 AC: 17 AN: 245970 Hom.: 0 AF XY: 0.0000821 AC XY: 11 AN XY: 133964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000555 AC: 81 AN: 1458790 Hom.: 0 Cov.: 32 AF XY: 0.0000510 AC XY: 37 AN XY: 725828

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000413 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.8825C>T (p.T2942M) alteration is located in exon 34 (coding exon 34) of the CELSR1 gene. This alteration results from a C to T substitution at nucleotide position 8825, causing the threonine (T) at amino acid position 2942 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.18
Sift	Uncertain	0.015	D
Sift4G	Benign	0.073	T
Polyphen		0.99	D
Vest4		0.29
MVP		0.41
MPC		0.21
ClinPred		0.10	T
GERP RS		0.64
Varity_R		0.050
gMVP		0.22

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: rs149360981; hg19: chr22-46760103; COSMIC: COSV53097420;