NM_001378328.1:c.6802A>G

Variant names:

• chr22-46384624-T-C
• rs6007897
• NM_001378328.1:c.6802A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (8376 hom., cov: 32)
  • Exomes 𝑓: 0.16 (24202 hom.)
• Consequence: CELSR1 NM_001378328.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.117
• Publications: 42 publications found

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]

CELSR1 Gene-Disease associations (from GenCC):

• lymphatic malformation 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neural tube defects, susceptibility to

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hydrops fetalis

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000297903 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3055407.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
CELSR1	NM_001378328.1	c.6802A>G	p.Thr2268Ala	missense_variant	Exon 20 of 35	ENST00000674500.2	NP_001365257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELSR1	ENST00000674500.2	c.6802A>G	p.Thr2268Ala	missense_variant	Exon 20 of 35		NM_001378328.1	ENSP00000501367.2

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

GnomAD2 exomes AF: 0.157 AC: 39241 AN: 250544 AF XY: 0.149

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 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

African (AFR) AF: 0.595 AC: 19888 AN: 33444

American (AMR) AF: 0.101 AC: 4524 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4474 AN: 26124

East Asian (EAS) AF: 0.0153 AC: 608 AN: 39684

South Asian (SAS) AF: 0.100 AC: 8622 AN: 86096

European-Finnish (FIN) AF: 0.113 AC: 6011 AN: 53376

Middle Eastern (MID) AF: 0.152 AC: 877 AN: 5760

European-Non Finnish (NFE) AF: 0.166 AC: 184315 AN: 1111602

Other (OTH) AF: 0.170 AC: 10258 AN: 60366

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

African (AFR) AF: 0.582 AC: 24127 AN: 41424

American (AMR) AF: 0.152 AC: 2316 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3464

East Asian (EAS) AF: 0.0155 AC: 80 AN: 5178

South Asian (SAS) AF: 0.0882 AC: 425 AN: 4816

European-Finnish (FIN) AF: 0.111 AC: 1178 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11258 AN: 67998

Other (OTH) AF: 0.218 AC: 461 AN: 2112

Alfa AF: 0.186 Hom.: 13825

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: no assertion criteria provided

Submissions by phenotype

CELSR1-related disorder Benign:1

Aug 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.12
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6007897; hg19: chr22-46780521; COSMIC: COSV53089133;