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, 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=0.0066734254).
• 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

Sel.	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	Q86UK5-2

Ensembl Transcripts

Sel.	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	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.2898C>G	p.Ser966Arg	missense	Exon 18 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.2898C>G		non_coding_transcript_exon	Exon 18 of 23	ENSP00000431981.1	A0A0C4DGE7

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not specified (1)

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;