1-109250455-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001408.3(CELSR2):c.376C>A(p.Gln126Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,720 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (33 hom.)
• Consequence: CELSR2 NM_001408.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.961

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CELSR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063497424).
• BP6: Variant 1-109250455-C-A is Benign according to our data. Variant chr1-109250455-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 782975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 538 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR2	NM_001408.3	c.376C>A	p.Gln126Lys	missense_variant	1/34	ENST00000271332.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR2	ENST00000271332.4	c.376C>A	p.Gln126Lys	missense_variant	1/34	1	NM_001408.3	P1

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 538 AN: 152230 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00304 AC: 762 AN: 250690 Hom.: 4 AF XY: 0.00326 AC XY: 442 AN XY: 135666

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00486 AC: 7097 AN: 1461372 Hom.: 33 Cov.: 71 AF XY: 0.00471 AC XY: 3422 AN XY: 726976

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.000983

Gnomad4 NFE exome AF: 0.00582

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.00353 AC: 538 AN: 152348 Hom.: 3 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74504

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00576

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00469 Hom.: 3

Bravo AF: 0.00339

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00291 AC: 353

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00492

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CELSR2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

CELSR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as likely 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.86	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Benign	0.66	T
Polyphen		0.12	B
Vest4		0.42
MVP		0.51
MPC		0.48
ClinPred		0.017	T
GERP RS		5.5
Varity_R		0.22
gMVP		0.55

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: rs62623708; hg19: chr1-109793077;