22-46504565-C-T

Variant names:

• chr22-46504565-C-T
• rs5768857
• NM_001378328.1:c.3544+29062G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378328.1(CELSR1):​c.3544+29062G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 150,534 control chromosomes in the GnomAD database, including 50,543 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (50543 hom., cov: 28)
• Consequence: CELSR1 NM_001378328.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.666
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 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.3544+29062G>A		intron	N/A	NP_001365257.1	A0A6I8PRU0
	CELSR1	NM_014246.4		c.3544+29062G>A		intron	N/A	NP_055061.1	Q9NYQ6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR1	ENST00000674500.2	MANE Select	c.3544+29062G>A		intron	N/A	ENSP00000501367.2	A0A6I8PRU0
	CELSR1	ENST00000262738.9	TSL:1	c.3544+29062G>A		intron	N/A	ENSP00000262738.3	Q9NYQ6-1
	CELSR1	ENST00000454637.2	TSL:1	c.3544+29062G>A		intron	N/A	ENSP00000414689.2	Q9NYQ6-2

Frequencies

GnomAD3 genomes AF: 0.818 AC: 123089 AN: 150418 Hom.: 50511 Cov.: 28

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.750

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.824

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.818 AC: 123172 AN: 150534 Hom.: 50543 Cov.: 28 AF XY: 0.822 AC XY: 60240 AN XY: 73324

African (AFR) AF: 0.835 AC: 34138 AN: 40870

American (AMR) AF: 0.843 AC: 12725 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2914 AN: 3468

East Asian (EAS) AF: 0.983 AC: 5052 AN: 5138

South Asian (SAS) AF: 0.746 AC: 3583 AN: 4800

European-Finnish (FIN) AF: 0.873 AC: 8679 AN: 9936

Middle Eastern (MID) AF: 0.818 AC: 239 AN: 292

European-Non Finnish (NFE) AF: 0.787 AC: 53431 AN: 67930

Other (OTH) AF: 0.822 AC: 1730 AN: 2104

Alfa AF: 0.796 Hom.: 197497

Bravo AF: 0.819

Asia WGS AF: 0.858 AC: 2987 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.68
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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: rs5768857; hg19: chr22-46900462;