chr22-46364133-CGTGCGCGAGGAT-C

Variant names:

• chr22-46364133-CGTGCGCGAGGAT-C
• rs375307146
• NM_001378328.1:c.8886_8897delATCCTCGCGCAC

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM4 PP3 BP6_Moderate BS1 BS2

The NM_001378328.1(CELSR1):​c.8886_8897delATCCTCGCGCAC​(p.Ser2963_Thr2966del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,612,304 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (13 hom.)
• Consequence: CELSR1 NM_001378328.1 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 9.05

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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001378328.1.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 22-46364133-CGTGCGCGAGGAT-C is Benign according to our data. Variant chr22-46364133-CGTGCGCGAGGAT-C is described in ClinVar as [Benign]. Clinvar id is 716653.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00804 (1225/152346) while in subpopulation AFR AF= 0.028 (1162/41574). AF 95% confidence interval is 0.0266. There are 20 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.8886_8897delATCCTCGCGCAC	p.Ser2963_Thr2966del	disruptive_inframe_deletion	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.8886_8897delATCCTCGCGCAC	p.Ser2963_Thr2966del	disruptive_inframe_deletion	Exon 34 of 35		NM_001378328.1	ENSP00000501367.2
CELSR1	ENST00000262738.9	c.8886_8897delATCCTCGCGCAC	p.Ser2963_Thr2966del	disruptive_inframe_deletion	Exon 34 of 35	1		ENSP00000262738.3
CELSR1	ENST00000473624.2	c.639_650delATCCTCGCGCAC	p.Ser214_Thr217del	disruptive_inframe_deletion	Exon 5 of 5	1		ENSP00000501353.1
CELSR1	ENST00000674159.1	n.2329_2340delATCCTCGCGCAC		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152228 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00203 AC: 504 AN: 248514 Hom.: 7 AF XY: 0.00149 AC XY: 201 AN XY: 135070

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000801 AC: 1169 AN: 1459958 Hom.: 13 AF XY: 0.000625 AC XY: 454 AN XY: 726260

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00804 AC: 1225 AN: 152346 Hom.: 20 Cov.: 33 AF XY: 0.00785 AC XY: 585 AN XY: 74504

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00411 Hom.: 0

Bravo AF: 0.00926

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

CELSR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs375307146; hg19: chr22-46760030;