22-46525238-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.3544+8389G>A		intron_variant		ENST00000674500.2
CELSR1	NM_014246.4	c.3544+8389G>A		intron_variant
CELSR1	XM_011530553.2	c.3544+8389G>A		intron_variant
CELSR1	XM_047441624.1	c.3544+8389G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.3544+8389G>A		intron_variant			NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.3544+8389G>A		intron_variant		1		P4
CELSR1	ENST00000454637.2	c.3544+8389G>A		intron_variant		1

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

Gnomad4 AFR AF: 0.465

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.0357

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.309

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

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

LitVar

Other links and lift over

dbSNP: rs4823557; hg19: chr22-46921135;