1-109250293-T-C

Position:

• chr1-109250293-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001408.3(CELSR2):​c.214T>C​(p.Cys72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CELSR2 NM_001408.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

CELSR2 (HGNC:3231): (cadherin EGF LAG seven-pass G-type receptor 2) 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. The specific function of this particular member has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32308847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR2	NM_001408.3	c.214T>C	p.Cys72Arg	missense_variant	1/34	ENST00000271332.4	NP_001399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELSR2	ENST00000271332.4	c.214T>C	p.Cys72Arg	missense_variant	1/34	1	NM_001408.3	ENSP00000271332.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 32

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

Apr 15, 2024

The c.214T>C (p.C72R) alteration is located in exon 1 (coding exon 1) of the CELSR2 gene. This alteration results from a T to C substitution at nucleotide position 214, causing the cysteine (C) at amino acid position 72 to be replaced by an arginine (R). 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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.61	T
Polyphen		0.98	D
Vest4		0.36
MutPred		0.62		Gain of disorder (P = 0.0239);
MVP		0.86
MPC		1.0
ClinPred		0.46	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-109792915;