chr22-46364189-C-T

Variant names:

• chr22-46364189-C-T
• rs35364389
• NM_001378328.1:c.8842G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378328.1(CELSR1):​c.8842G>A​(p.Gly2948Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,611,808 control chromosomes in the GnomAD database, including 22,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4691 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17940 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.729
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• lymphatic malformation 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neural tube defects, susceptibility to

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hydrops fetalis

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.2604756E-4).
• BP6: Variant 22-46364189-C-T is Benign according to our data. Variant chr22-46364189-C-T is described in ClinVar as Benign. ClinVar VariationId is 1257697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378328.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR1	NM_001378328.1	MANE Select	c.8842G>A	p.Gly2948Ser	missense	Exon 34 of 35	NP_001365257.1	A0A6I8PRU0
	CELSR1	NM_014246.4		c.8842G>A	p.Gly2948Ser	missense	Exon 34 of 35	NP_055061.1	Q9NYQ6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR1	ENST00000674500.2	MANE Select	c.8842G>A	p.Gly2948Ser	missense	Exon 34 of 35	ENSP00000501367.2	A0A6I8PRU0
	CELSR1	ENST00000262738.9	TSL:1	c.8842G>A	p.Gly2948Ser	missense	Exon 34 of 35	ENSP00000262738.3	Q9NYQ6-1
	CELSR1	ENST00000473624.2	TSL:1	c.595G>A	p.Gly199Ser	missense	Exon 5 of 5	ENSP00000501353.1	A0A6I8PL36

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32406 AN: 152124 Hom.: 4674 Cov.: 33

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0584

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.138 AC: 33991 AN: 247156 AF XY: 0.133

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.0816

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.000494

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.147 AC: 214383 AN: 1459566 Hom.: 17940 Cov.: 33 AF XY: 0.144 AC XY: 104402 AN XY: 726102

African (AFR) AF: 0.412 AC: 13770 AN: 33450

American (AMR) AF: 0.0870 AC: 3884 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2864 AN: 26114

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.0675 AC: 5819 AN: 86248

European-Finnish (FIN) AF: 0.183 AC: 9414 AN: 51544

Middle Eastern (MID) AF: 0.108 AC: 621 AN: 5766

European-Non Finnish (NFE) AF: 0.152 AC: 169016 AN: 1111748

Other (OTH) AF: 0.149 AC: 8986 AN: 60340

GnomAD4 genome AF: 0.213 AC: 32471 AN: 152242 Hom.: 4691 Cov.: 33 AF XY: 0.210 AC XY: 15608 AN XY: 74440

African (AFR) AF: 0.401 AC: 16660 AN: 41506

American (AMR) AF: 0.129 AC: 1970 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5194

South Asian (SAS) AF: 0.0578 AC: 279 AN: 4828

European-Finnish (FIN) AF: 0.194 AC: 2057 AN: 10608

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10575 AN: 68016

Other (OTH) AF: 0.171 AC: 361 AN: 2114

Alfa AF: 0.164 Hom.: 3208

Bravo AF: 0.217

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.158 AC: 610

ESP6500AA AF: 0.387 AC: 1704

ESP6500EA AF: 0.144 AC: 1241

ExAC AF: 0.142 AC: 17227

Asia WGS AF: 0.0580 AC: 204 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CELSR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.72
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.00093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.73
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.24
Sift	Benign	0.74	T
Sift4G	Benign	0.62	T
Polyphen		0.0060	B
Vest4		0.019
MPC		0.17
ClinPred		0.0018	T
GERP RS		-0.079
Varity_R		0.037
gMVP		0.056
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35364389; hg19: chr22-46760086; COSMIC: COSV53086583;