4-5576374-G-C

Variant names:

• chr4-5576374-G-C
• rs73074138
• NM_147127.5:c.3138C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):​c.3138C>G​(p.Ser1046Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,094 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1046S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (23 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.426
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066734254).
• BP6: Variant 4-5576374-G-C is Benign according to our data. Variant chr4-5576374-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.008 (1219/152308) while in subpopulation AFR AF = 0.0234 (973/41568). AF 95% confidence interval is 0.0222. There are 13 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.3138C>G	p.Ser1046Arg	missense	Exon 18 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.2898C>G	p.Ser966Arg	missense	Exon 18 of 22	NP_001159608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.3138C>G	p.Ser1046Arg	missense	Exon 18 of 22	ENSP00000342144.5
	EVC2	ENST00000310917.6	TSL:1	c.2898C>G	p.Ser966Arg	missense	Exon 18 of 22	ENSP00000311683.2
	EVC2	ENST00000475313.5	TSL:1	n.2898C>G		non_coding_transcript_exon	Exon 18 of 23	ENSP00000431981.1

Frequencies

GnomAD3 genomes AF: 0.00799 AC: 1216 AN: 152190 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00340 AC: 853 AN: 250920 AF XY: 0.00283

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00533

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00168 AC: 2463 AN: 1461786 Hom.: 23 Cov.: 35 AF XY: 0.00164 AC XY: 1195 AN XY: 727210

African (AFR) AF: 0.0246 AC: 823 AN: 33480

American (AMR) AF: 0.00530 AC: 237 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53370

Middle Eastern (MID) AF: 0.0225 AC: 130 AN: 5768

European-Non Finnish (NFE) AF: 0.000781 AC: 868 AN: 1111974

Other (OTH) AF: 0.00366 AC: 221 AN: 60388

GnomAD4 genome AF: 0.00800 AC: 1219 AN: 152308 Hom.: 13 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74468

African (AFR) AF: 0.0234 AC: 973 AN: 41568

American (AMR) AF: 0.00915 AC: 140 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68030

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00904

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00362 AC: 440

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Sep 07, 2017

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;C0457013:Curry-Hall syndrome Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ellis-van Creveld syndrome Benign:1

Jan 13, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.43
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.011	D
Polyphen		0.87	P
Vest4		0.37
MutPred		0.25		Gain of MoRF binding (P = 0.0079)
MVP		0.72
MPC		0.13
ClinPred		0.048	T
GERP RS		-0.22
Varity_R		0.13
gMVP		0.15
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs73074138; hg19: chr4-5578101;