rs60121553

Positions:

• chr4-5622803-T-C

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.2235A>G​(p.Glu745=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,613,900 control chromosomes in the GnomAD database, including 2,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1437 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1376 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.17

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=-0.69).
• BP6: Variant 4-5622803-T-C is Benign according to our data. Variant chr4-5622803-T-C is described in ClinVar as [Benign]. Clinvar id is 262611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2235A>G	p.Glu745=	synonymous_variant	14/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.2235A>G	p.Glu745=	synonymous_variant	14/22	1	NM_147127.5	ENSP00000342144	P2
EVC2	ENST00000310917.6	c.1995A>G	p.Glu665=	synonymous_variant	14/22	1		ENSP00000311683	A2
EVC2	ENST00000475313.5	c.1995A>G	p.Glu665=	synonymous_variant, NMD_transcript_variant	14/23	1		ENSP00000431981
EVC2	ENST00000509670.1	c.*628A>G		3_prime_UTR_variant, NMD_transcript_variant	15/23	1		ENSP00000423876

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 11907 AN: 151900 Hom.: 1436 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0248 AC: 6242 AN: 251330 Hom.: 595 AF XY: 0.0194 AC XY: 2642 AN XY: 135868

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00852

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0149 AC: 21815 AN: 1461882 Hom.: 1376 Cov.: 32 AF XY: 0.0137 AC XY: 9985 AN XY: 727244

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.00662

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00868

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0785 AC: 11931 AN: 152018 Hom.: 1437 Cov.: 32 AF XY: 0.0749 AC XY: 5566 AN XY: 74316

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.0408

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00815

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0473 Hom.: 291

Bravo AF: 0.0910

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 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;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.7
DANN	Benign	0.46

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: rs60121553; hg19: chr4-5624530;