rs730469

chr4-5622943-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T699T) has been classified as Likely benign.

• 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:4
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
EVC2	NM_147127.5	c.2095A>G	p.Thr699Ala	missense_variant	14/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.2095A>G	p.Thr699Ala	missense_variant	14/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.1855A>G	p.Thr619Ala	missense_variant	14/22	1		A2
EVC2	ENST00000475313.5	c.1855A>G	p.Thr619Ala	missense_variant, NMD_transcript_variant	14/23	1
EVC2	ENST00000509670.1	c.*488A>G		3_prime_UTR_variant, NMD_transcript_variant	15/23	1

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

GnomAD3 exomes AF: 0.366 AC: 91740 AN: 250438 Hom.: 19641 AF XY: 0.351 AC XY: 47524 AN XY: 135584

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 SAS exome AF: 0.289

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

Gnomad4 AFR exome AF: 0.807

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.609

Gnomad4 SAS exome AF: 0.285

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.329

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

Gnomad4 AFR AF: 0.788

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.389

Alfa AF: 0.311 Hom.: 20617

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ellis-van Creveld syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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;.
MutationTaster	Benign	1.0	P;P;P
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

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