rs141489111

Variant names:

• chr1-109269470-G-A
• rs141489111
• NM_001408.3:c.6859G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-109269470-G-A
• chr1-109269470-G-C
• chr1-109269470-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001408.3(CELSR2):​c.6859G>A​(p.Val2287Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,936 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: CELSR2 NM_001408.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 3.01
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029229522).
• BS2: High AC in GnomAd4 at 161 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001408.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR2	NM_001408.3	MANE Select	c.6859G>A	p.Val2287Ile	missense	Exon 21 of 34	NP_001399.1	Q9HCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELSR2	ENST00000271332.4	TSL:1 MANE Select	c.6859G>A	p.Val2287Ile	missense	Exon 21 of 34	ENSP00000271332.3	Q9HCU4

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000911 AC: 229 AN: 251248 AF XY: 0.000979

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00172 AC: 2515 AN: 1461770 Hom.: 3 Cov.: 33 AF XY: 0.00164 AC XY: 1193 AN XY: 727208

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00215 AC: 2390 AN: 1111994

Other (OTH) AF: 0.00103 AC: 62 AN: 60396

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.000915 AC XY: 68 AN XY: 74330

African (AFR) AF: 0.000459 AC: 19 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.00110

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000857 AC: 104

EpiCase AF: 0.00125

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	CELSR2-related disorder (1)
-	1	-	Idiopathic scoliosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.024
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.062
Sift	Benign	0.23	T
Sift4G	Benign	0.10	T
Polyphen		0.19	B
Vest4		0.45
MVP		0.39
MPC		0.38
ClinPred		0.011	T
GERP RS		4.4
Varity_R		0.086
gMVP		0.11
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs141489111; hg19: chr1-109812092; COSMIC: COSV54767098; COSMIC: COSV54767098;