chr22-46364032-C-A

Variant names:

• chr22-46364032-C-A
• rs376054333
• NM_001378328.1:c.8999G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378328.1(CELSR1):​c.8999G>T​(p.Arg3000Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3000H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 0 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: Illumina, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12817857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8999G>T	p.Arg3000Leu	missense_variant	Exon 34 of 35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELSR1	ENST00000674500.2	c.8999G>T	p.Arg3000Leu	missense_variant	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8999G>T	p.Arg3000Leu	missense_variant	Exon 34 of 35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.752G>T	p.Arg251Leu	missense_variant	Exon 5 of 5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2442G>T		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458718 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725530

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111140

Other (OTH) AF: 0.00 AC: 0 AN: 60186

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.073	T
Sift4G	Benign	0.16	T
Polyphen		0.30	B
Vest4		0.21
MutPred		0.30		Loss of MoRF binding (P = 0.0138);
MVP		0.47
MPC		0.27
ClinPred		0.39	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.11
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs376054333; hg19: chr22-46759929;