rs6007897

chr22-46384624-T-Cchr22-46384624-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378328.1(CELSR1):c.6802A>G(p.Thr2268Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,128 control chromosomes in the GnomAD database, including 32,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2268S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.27 (8376 hom., cov: 32)
  • Exomes 𝑓: 0.16 (24202 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.117

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0373151E-5).
• BP6: Variant 22-46384624-T-C is Benign according to our data. Variant chr22-46384624-T-C is described in ClinVar as [Benign]. Clinvar id is 3055407.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-46384624-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR1	NM_001378328.1	c.6802A>G	p.Thr2268Ala	missense_variant	20/35	ENST00000674500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR1	ENST00000674500.2	c.6802A>G	p.Thr2268Ala	missense_variant	20/35		NM_001378328.1	A2
CELSR1	ENST00000262738.9	c.6802A>G	p.Thr2268Ala	missense_variant	20/35	1		P4
CELSR1	ENST00000674341.1	n.1879A>G		non_coding_transcript_exon_variant	12/19
CELSR1	ENST00000674379.1	n.159A>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40599 AN: 151946 Hom.: 8345 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0896

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.221

GnomAD3 exomes AF: 0.157 AC: 39241 AN: 250544 Hom.: 5050 AF XY: 0.149 AC XY: 20177 AN XY: 135466

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0140

Gnomad SAS exome AF: 0.0985

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.164 AC: 239577 AN: 1461064 Hom.: 24202 Cov.: 32 AF XY: 0.161 AC XY: 116799 AN XY: 726818

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.0153

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.267 AC: 40674 AN: 152064 Hom.: 8376 Cov.: 32 AF XY: 0.259 AC XY: 19242 AN XY: 74352

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.0882

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.218

Alfa AF: 0.173 Hom.: 5706

Bravo AF: 0.284

TwinsUK AF: 0.161 AC: 598

ALSPAC AF: 0.169 AC: 650

ESP6500AA AF: 0.578 AC: 2548

ESP6500EA AF: 0.154 AC: 1325

ExAC AF: 0.166 AC: 20100

Asia WGS AF: 0.0870 AC: 305 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.166

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CELSR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 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
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	1.1
Dann	Benign	0.21
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.066	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.038
Sift	Benign	0.79	T
Sift4G	Benign	0.75	T
Polyphen		0.0030	B
Vest4		0.016
MPC		0.17
ClinPred		0.0012	T
GERP RS		0.59
Varity_R		0.025
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6007897; hg19: chr22-46780521; COSMIC: COSV53089133;