rs77793386

chr4-5663193-G-Achr4-5663193-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_147127.5(EVC2):c.1059C>T(p.Gly353=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,614,082 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G353G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (150 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (144 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.70

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-5663193-G-A is Benign according to our data. Variant chr4-5663193-G-A is described in ClinVar as [Benign]. Clinvar id is 349091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.1059C>T	p.Gly353=	synonymous_variant	9/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.1059C>T	p.Gly353=	synonymous_variant	9/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.819C>T	p.Gly273=	synonymous_variant	9/22	1		A2
EVC2	ENST00000475313.5	c.819C>T	p.Gly273=	synonymous_variant, NMD_transcript_variant	9/23	1
EVC2	ENST00000509670.1	c.819C>T	p.Gly273=	synonymous_variant, NMD_transcript_variant	10/23	1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3714 AN: 152100 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00605 AC: 1521 AN: 251486 Hom.: 62 AF XY: 0.00436 AC XY: 593 AN XY: 135916

Gnomad AFR exome AF: 0.0839

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00243 AC: 3555 AN: 1461864 Hom.: 144 Cov.: 31 AF XY: 0.00206 AC XY: 1500 AN XY: 727232

Gnomad4 AFR exome AF: 0.0863

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.0245 AC: 3724 AN: 152218 Hom.: 150 Cov.: 32 AF XY: 0.0229 AC XY: 1703 AN XY: 74442

Gnomad4 AFR AF: 0.0848

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.00984 Hom.: 34

Bravo AF: 0.0276

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Ellis-van Creveld syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.19
Dann	Benign	0.53

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: rs77793386; hg19: chr4-5664920;