1-109250351-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001408.3(CELSR2):c.272G>A(p.Arg91Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,482 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (18 hom.)
• Consequence: CELSR2 NM_001408.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.934

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CELSR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035412908).
• BP6: Variant 1-109250351-G-A is Benign according to our data. Variant chr1-109250351-G-A is described in ClinVar as [Benign]. Clinvar id is 791805.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00896 (1364/152308) while in subpopulation AFR AF= 0.0313 (1301/41574). AF 95% confidence interval is 0.0299. There are 12 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR2	NM_001408.3	c.272G>A	p.Arg91Lys	missense_variant	1/34	ENST00000271332.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR2	ENST00000271332.4	c.272G>A	p.Arg91Lys	missense_variant	1/34	1	NM_001408.3	P1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152190 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00232 AC: 582 AN: 250614 Hom.: 8 AF XY: 0.00177 AC XY: 240 AN XY: 135646

Gnomad AFR exome AF: 0.0321

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000855 AC: 1250 AN: 1461174 Hom.: 18 Cov.: 69 AF XY: 0.000742 AC XY: 539 AN XY: 726890

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00896 AC: 1364 AN: 152308 Hom.: 12 Cov.: 32 AF XY: 0.00884 AC XY: 658 AN XY: 74472

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00244 Hom.: 6

Bravo AF: 0.0102

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.34	T
Polyphen		0.023	B
Vest4		0.13
MVP		0.31
MPC		0.39
ClinPred		0.0044	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs112983744; hg19: chr1-109792973; COSMIC: COSV54767720;