22-46525238-C-T

Variant names:

• chr22-46525238-C-T
• rs4823557
• NM_001378328.1:c.3544+8389G>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+8389G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,052 control chromosomes in the GnomAD database, including 9,031 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 0.33 (9031 hom., cov: 33)
• Consequence: CELSR1 NM_001378328.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.786
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.3544+8389G>A		intron_variant	Intron 1 of 34	ENST00000674500.2	NP_001365257.1
CELSR1	NM_014246.4	c.3544+8389G>A		intron_variant	Intron 1 of 34		NP_055061.1
CELSR1	XM_047441624.1	c.3544+8389G>A		intron_variant	Intron 1 of 33		XP_047297580.1
CELSR1	XM_011530553.2	c.3544+8389G>A		intron_variant	Intron 1 of 16		XP_011528855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELSR1	ENST00000674500.2	c.3544+8389G>A		intron_variant	Intron 1 of 34		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.3544+8389G>A		intron_variant	Intron 1 of 34	1		ENSP00000262738.3
CELSR1	ENST00000454637.2	c.3544+8389G>A		intron_variant	Intron 1 of 2	1		ENSP00000414689.2

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50206 AN: 151934 Hom.: 9019 Cov.: 33

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.330 AC: 50238 AN: 152052 Hom.: 9031 Cov.: 33 AF XY: 0.326 AC XY: 24232 AN XY: 74330

African (AFR) AF: 0.465 AC: 19265 AN: 41456

American (AMR) AF: 0.237 AC: 3628 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3472

East Asian (EAS) AF: 0.0357 AC: 185 AN: 5188

South Asian (SAS) AF: 0.225 AC: 1085 AN: 4818

European-Finnish (FIN) AF: 0.318 AC: 3355 AN: 10538

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20708 AN: 67980

Other (OTH) AF: 0.309 AC: 653 AN: 2110

Alfa AF: 0.330 Hom.: 1053

Bravo AF: 0.329

Asia WGS AF: 0.148 AC: 514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.3
DANN	Benign	0.88
PhyloP100		0.79
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: rs4823557; hg19: chr22-46921135;