rs4689278

Variant names:

• chr4-5689175-T-C
• rs4689278
• NM_147127.5:c.688A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-5689175-T-C
• chr4-5689175-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147127.5(EVC2):​c.688A>G​(p.Ser230Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,956 control chromosomes in the GnomAD database, including 41,951 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S230R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (3753 hom., cov: 33)
  • Exomes 𝑓: 0.23 (38198 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.22
• Publications: 33 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004810661).
• BP6: Variant 4-5689175-T-C is Benign according to our data. Variant chr4-5689175-T-C is described in ClinVar as Benign. ClinVar VariationId is 262620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.688A>G	p.Ser230Gly	missense	Exon 5 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.448A>G	p.Ser150Gly	missense	Exon 5 of 22	NP_001159608.1	Q86UK5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.688A>G	p.Ser230Gly	missense	Exon 5 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.448A>G	p.Ser150Gly	missense	Exon 5 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.448A>G		non_coding_transcript_exon	Exon 5 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33675 AN: 152042 Hom.: 3746 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.239 AC: 60173 AN: 251426 AF XY: 0.241

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.398

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.226 AC: 330040 AN: 1461796 Hom.: 38198 Cov.: 33 AF XY: 0.227 AC XY: 164757 AN XY: 727188

African (AFR) AF: 0.188 AC: 6279 AN: 33478

American (AMR) AF: 0.250 AC: 11188 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5855 AN: 26132

East Asian (EAS) AF: 0.347 AC: 13789 AN: 39696

South Asian (SAS) AF: 0.258 AC: 22212 AN: 86258

European-Finnish (FIN) AF: 0.227 AC: 12118 AN: 53394

Middle Eastern (MID) AF: 0.215 AC: 1242 AN: 5768

European-Non Finnish (NFE) AF: 0.219 AC: 243532 AN: 1111960

Other (OTH) AF: 0.229 AC: 13825 AN: 60390

GnomAD4 genome AF: 0.221 AC: 33693 AN: 152160 Hom.: 3753 Cov.: 33 AF XY: 0.225 AC XY: 16703 AN XY: 74390

African (AFR) AF: 0.196 AC: 8124 AN: 41522

American (AMR) AF: 0.238 AC: 3640 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 803 AN: 3470

East Asian (EAS) AF: 0.386 AC: 1992 AN: 5166

South Asian (SAS) AF: 0.273 AC: 1313 AN: 4818

European-Finnish (FIN) AF: 0.229 AC: 2421 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14725 AN: 67994

Other (OTH) AF: 0.232 AC: 489 AN: 2112

Alfa AF: 0.220 Hom.: 17222

Bravo AF: 0.222

TwinsUK AF: 0.224 AC: 831

ALSPAC AF: 0.226 AC: 871

ESP6500AA AF: 0.201 AC: 887

ESP6500EA AF: 0.216 AC: 1856

ExAC AF: 0.236 AC: 28714

Asia WGS AF: 0.302 AC: 1047 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.222

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ellis-van Creveld syndrome (2)
-	-	2	not specified (2)
-	-	1	Curry-Hall syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.099
Sift	Benign	0.13	T
Sift4G	Uncertain	0.025	D
Polyphen		0.081	B
Vest4		0.042
MPC		0.020
ClinPred		0.0024	T
GERP RS		1.9
Varity_R		0.067
gMVP		0.47
Mutation Taster		=99/1	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: rs4689278; hg19: chr4-5690902; COSMIC: COSV60389850;