chr22-46418774-C-T

Variant names:

• chr22-46418774-C-T
• rs6008817
• NM_001378328.1:c.4612-7015G>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.4612-7015G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,178 control chromosomes in the GnomAD database, including 12,925 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 0.35 (12925 hom., cov: 33)
• Consequence: CELSR1 NM_001378328.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 11 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR1	NM_001378328.1	MANE Select	c.4612-7015G>A		intron	N/A	NP_001365257.1
	CELSR1	NM_014246.4		c.4612-7015G>A		intron	N/A	NP_055061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR1	ENST00000674500.2	MANE Select	c.4612-7015G>A		intron	N/A	ENSP00000501367.2
	CELSR1	ENST00000262738.9	TSL:1	c.4612-7015G>A		intron	N/A	ENSP00000262738.3

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52619 AN: 152060 Hom.: 12881 Cov.: 33

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.293

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

GnomAD4 genome AF: 0.346 AC: 52711 AN: 152178 Hom.: 12925 Cov.: 33 AF XY: 0.335 AC XY: 24946 AN XY: 74384

African (AFR) AF: 0.700 AC: 29056 AN: 41508

American (AMR) AF: 0.208 AC: 3178 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3470

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5188

South Asian (SAS) AF: 0.168 AC: 809 AN: 4820

European-Finnish (FIN) AF: 0.159 AC: 1685 AN: 10592

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16290 AN: 67988

Other (OTH) AF: 0.290 AC: 612 AN: 2112

Alfa AF: 0.264 Hom.: 27672

Bravo AF: 0.362

Asia WGS AF: 0.131 AC: 456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.56
DANN	Benign	0.83
PhyloP100		-1.0
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: rs6008817; hg19: chr22-46814671;