rs730469

Variant names:

• chr4-5622943-T-C
• rs730469
• NM_147127.5:c.2095A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147127.5(EVC2):​c.2095A>G​(p.Thr699Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,758 control chromosomes in the GnomAD database, including 94,610 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T699M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.45 (18957 hom., cov: 32)
  • Exomes 𝑓: 0.31 (75653 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.54
• Publications: 34 publications found

Genes affected

EVC2 (HGNC:19747): (EvC ciliary complex subunit 2) This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

EVC2 Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0240383E-6).
• BP6: Variant 4-5622943-T-C is Benign according to our data. Variant chr4-5622943-T-C is described in ClinVar as Benign. ClinVar VariationId is 262610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2095A>G	p.Thr699Ala	missense_variant	Exon 14 of 22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.2095A>G	p.Thr699Ala	missense_variant	Exon 14 of 22	1	NM_147127.5	ENSP00000342144.5

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67848 AN: 151906 Hom.: 18912 Cov.: 32

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.394

GnomAD2 exomes AF: 0.366 AC: 91740 AN: 250438 AF XY: 0.351

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.633

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.305 AC: 445835 AN: 1461732 Hom.: 75653 Cov.: 66 AF XY: 0.303 AC XY: 219983 AN XY: 727156

African (AFR) AF: 0.807 AC: 27026 AN: 33476

American (AMR) AF: 0.419 AC: 18754 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6912 AN: 26136

East Asian (EAS) AF: 0.609 AC: 24170 AN: 39698

South Asian (SAS) AF: 0.285 AC: 24550 AN: 86250

European-Finnish (FIN) AF: 0.339 AC: 18084 AN: 53372

Middle Eastern (MID) AF: 0.321 AC: 1853 AN: 5764

European-Non Finnish (NFE) AF: 0.274 AC: 304628 AN: 1111930

Other (OTH) AF: 0.329 AC: 19858 AN: 60386

GnomAD4 genome AF: 0.447 AC: 67942 AN: 152026 Hom.: 18957 Cov.: 32 AF XY: 0.450 AC XY: 33415 AN XY: 74300

African (AFR) AF: 0.788 AC: 32685 AN: 41486

American (AMR) AF: 0.408 AC: 6228 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 921 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3149 AN: 5160

South Asian (SAS) AF: 0.300 AC: 1445 AN: 4820

European-Finnish (FIN) AF: 0.351 AC: 3704 AN: 10562

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18681 AN: 67944

Other (OTH) AF: 0.389 AC: 821 AN: 2112

Alfa AF: 0.336 Hom.: 34770

Bravo AF: 0.472

TwinsUK AF: 0.265 AC: 983

ALSPAC AF: 0.273 AC: 1053

ESP6500AA AF: 0.773 AC: 3407

ESP6500EA AF: 0.278 AC: 2393

ExAC AF: 0.369 AC: 44836

Asia WGS AF: 0.478 AC: 1661 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.283

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ellis-van Creveld syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.3
DANN	Benign	0.15
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N;.
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.011
MPC		0.020
ClinPred		0.00073	T
GERP RS		0.37
Varity_R		0.022
gMVP		0.039
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs730469; hg19: chr4-5624670; COSMIC: COSV60389754;