22-46364179-C-G

Variant names:

• chr22-46364179-C-G
• NM_001378328.1:c.8852G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378328.1(CELSR1):​c.8852G>C​(p.Arg2951Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8852G>C	p.Arg2951Pro	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.8852G>C	p.Arg2951Pro	missense_variant	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8852G>C	p.Arg2951Pro	missense_variant	Exon 34 of 35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.605G>C	p.Arg202Pro	missense_variant	Exon 5 of 5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2295G>C		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459800 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.34
Sift	Benign	0.046	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.21		Gain of methylation at K2953 (P = 0.0436);
MVP		0.64
MPC		0.85
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.51
gMVP		0.35

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: chr22-46760076; COSMIC: COSV53085594;