chr22-46364159-C-T

Variant names:

• chr22-46364159-C-T
• rs2078738622
• NM_001378328.1:c.8872G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001378328.1(CELSR1):​c.8872G>A​(p.Glu2958Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8872G>A	p.Glu2958Lys	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.8872G>A	p.Glu2958Lys	missense_variant	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8872G>A	p.Glu2958Lys	missense_variant	Exon 34 of 35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.625G>A	p.Glu209Lys	missense_variant	Exon 5 of 5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2315G>A		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459978 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8872G>A (p.E2958K) alteration is located in exon 34 (coding exon 34) of the CELSR1 gene. This alteration results from a G to A substitution at nucleotide position 8872, causing the glutamic acid (E) at amino acid position 2958 to be replaced by a lysine (K). 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	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.073
Sift	Benign	0.35	T
Sift4G	Benign	0.96	T
Polyphen		0.013	B
Vest4		0.24
MutPred		0.17		Gain of methylation at E2958 (P = 8e-04);
MVP		0.44
MPC		0.19
ClinPred		0.19	T
GERP RS		3.6
Varity_R		0.098
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2078738622; hg19: chr22-46760056;