1-109272630-A-G

Position:

• chr1-109272630-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001408.3(CELSR2):​c.8055-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,610,362 control chromosomes in the GnomAD database, including 76,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7667 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68980 hom.)
• Consequence: CELSR2 NM_001408.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001355
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.677

Genes affected

CELSR2 (HGNC:3231): (cadherin EGF LAG seven-pass G-type receptor 2) 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. The specific function of this particular member has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-109272630-A-G is Benign according to our data. Variant chr1-109272630-A-G is described in ClinVar as [Benign]. Clinvar id is 1530644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR2	NM_001408.3	c.8055-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000271332.4	NP_001399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELSR2	ENST00000271332.4	c.8055-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001408.3	ENSP00000271332	P1
CELSR2	ENST00000489018.1	n.1971A>G		non_coding_transcript_exon_variant	5/9	5
CELSR2	ENST00000498157.1	n.851-10A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47126 AN: 151878 Hom.: 7656 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0642

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.294

GnomAD3 exomes AF: 0.282 AC: 69921 AN: 247816 Hom.: 10573 AF XY: 0.283 AC XY: 38119 AN XY: 134532

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.0648

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.304 AC: 442987 AN: 1458364 Hom.: 68980 Cov.: 33 AF XY: 0.302 AC XY: 219069 AN XY: 725640

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.0692

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.310 AC: 47164 AN: 151998 Hom.: 7667 Cov.: 32 AF XY: 0.310 AC XY: 23032 AN XY: 74302

Gnomad4 AFR AF: 0.336

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.0639

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.346

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.292

Alfa AF: 0.309 Hom.: 4498

Bravo AF: 0.307

Asia WGS AF: 0.175 AC: 609 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CELSR2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.7
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs611917; hg19: chr1-109815252; COSMIC: COSV54773351;