rs73198153

Positions:

• chr4-5622977-A-G

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.2061T>C​(p.Arg687=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,613,516 control chromosomes in the GnomAD database, including 5,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1523 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3769 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.708

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=-0.74).
• BP6: Variant 4-5622977-A-G is Benign according to our data. Variant chr4-5622977-A-G is described in ClinVar as [Benign]. Clinvar id is 262609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.708 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2061T>C	p.Arg687=	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.2061T>C	p.Arg687=	synonymous_variant	14/22	1	NM_147127.5	ENSP00000342144	P2
EVC2	ENST00000310917.6	c.1821T>C	p.Arg607=	synonymous_variant	14/22	1		ENSP00000311683	A2
EVC2	ENST00000475313.5	c.1821T>C	p.Arg607=	synonymous_variant, NMD_transcript_variant	14/23	1		ENSP00000431981
EVC2	ENST00000509670.1	c.*454T>C		3_prime_UTR_variant, NMD_transcript_variant	15/23	1		ENSP00000423876

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16588 AN: 152020 Hom.: 1522 Cov.: 33

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0603

Gnomad OTH AF: 0.0798

GnomAD3 exomes AF: 0.0686 AC: 17071 AN: 248850 Hom.: 999 AF XY: 0.0692 AC XY: 9335 AN XY: 134986

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.00512

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0608 AC: 88808 AN: 1461378 Hom.: 3769 Cov.: 35 AF XY: 0.0623 AC XY: 45292 AN XY: 727012

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.0439

Gnomad4 ASJ exome AF: 0.0455

Gnomad4 EAS exome AF: 0.00325

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.0432

Gnomad4 NFE exome AF: 0.0546

Gnomad4 OTH exome AF: 0.0667

GnomAD4 genome AF: 0.109 AC: 16610 AN: 152138 Hom.: 1523 Cov.: 33 AF XY: 0.106 AC XY: 7865 AN XY: 74368

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0582

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0461

Gnomad4 NFE AF: 0.0603

Gnomad4 OTH AF: 0.0818

Alfa AF: 0.0843 Hom.: 469

Bravo AF: 0.115

Asia WGS AF: 0.0840 AC: 291 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0627

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	Apr 15, 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 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. -

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

- -

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	-0.74
CADD	Benign	1.3
DANN	Benign	0.43

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: rs73198153; hg19: chr4-5624704;