rs73198153

Variant names:

• chr4-5622977-A-G
• rs73198153
• NM_147127.5:c.2061T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_147127.5(EVC2):​c.2061T>C​(p.Arg687Arg) 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
• Publications: 6 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 -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 VariationId 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 rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2061T>C	p.Arg687Arg	synonymous_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.2061T>C	p.Arg687Arg	synonymous_variant	Exon 14 of 22	1	NM_147127.5	ENSP00000342144.5

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

GnomAD2 exomes AF: 0.0686 AC: 17071 AN: 248850 AF XY: 0.0692

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 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

African (AFR) AF: 0.249 AC: 8348 AN: 33470

American (AMR) AF: 0.0439 AC: 1964 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 1189 AN: 26128

East Asian (EAS) AF: 0.00325 AC: 129 AN: 39694

South Asian (SAS) AF: 0.113 AC: 9726 AN: 86236

European-Finnish (FIN) AF: 0.0432 AC: 2304 AN: 53342

Middle Eastern (MID) AF: 0.0740 AC: 426 AN: 5760

European-Non Finnish (NFE) AF: 0.0546 AC: 60697 AN: 1111642

Other (OTH) AF: 0.0667 AC: 4025 AN: 60386

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

African (AFR) AF: 0.246 AC: 10196 AN: 41486

American (AMR) AF: 0.0582 AC: 890 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3472

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5172

South Asian (SAS) AF: 0.104 AC: 501 AN: 4816

European-Finnish (FIN) AF: 0.0461 AC: 488 AN: 10578

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0603 AC: 4100 AN: 68008

Other (OTH) AF: 0.0818 AC: 173 AN: 2116

Alfa AF: 0.0899 Hom.: 839

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 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. -

Ellis-van Creveld syndrome Benign:1

Jan 12, 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. -

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

- -

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
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		-0.71
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: rs73198153; hg19: chr4-5624704;