rs73063795

Variant names:

• chr4-5640600-T-C
• rs73063795
• NM_147127.5:c.1384A>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.1384A>G​(p.Thr462Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,614,130 control chromosomes in the GnomAD database, including 53 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T462T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (26 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.552
• 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=0.0046666563).
• BP6: Variant 4-5640600-T-C is Benign according to our data. Variant chr4-5640600-T-C is described in ClinVar as Benign. ClinVar VariationId is 235428.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 = 0.0115 (1745/152244) while in subpopulation AFR AF = 0.0332 (1377/41530). AF 95% confidence interval is 0.0317. There are 27 homozygotes in GnomAd4. There are 845 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.1384A>G	p.Thr462Ala	missense	Exon 10 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.1144A>G	p.Thr382Ala	missense	Exon 10 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.1384A>G	p.Thr462Ala	missense	Exon 10 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1144A>G	p.Thr382Ala	missense	Exon 10 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1144A>G		non_coding_transcript_exon	Exon 10 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1727 AN: 152126 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00433 AC: 1089 AN: 251470 AF XY: 0.00361

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00212 AC: 3096 AN: 1461886 Hom.: 26 Cov.: 34 AF XY: 0.00199 AC XY: 1447 AN XY: 727242

African (AFR) AF: 0.0340 AC: 1138 AN: 33480

American (AMR) AF: 0.00827 AC: 370 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 172 AN: 26136

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

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00988 AC: 57 AN: 5768

European-Non Finnish (NFE) AF: 0.000933 AC: 1037 AN: 1112010

Other (OTH) AF: 0.00512 AC: 309 AN: 60396

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 152244 Hom.: 27 Cov.: 32 AF XY: 0.0113 AC XY: 845 AN XY: 74452

African (AFR) AF: 0.0332 AC: 1377 AN: 41530

American (AMR) AF: 0.0158 AC: 241 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68030

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.00844 Hom.: 19

Bravo AF: 0.0130

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0329 AC: 145

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00435 AC: 528

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.0
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.55
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.062	T
Sift4G	Benign	0.26	T
Polyphen		0.45	P
Vest4		0.085
MVP		0.68
MPC		0.020
ClinPred		0.011	T
GERP RS		-4.3
Varity_R		0.057
gMVP		0.28
Mutation Taster		=97/3	polymorphism

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: rs73063795; hg19: chr4-5642327; COSMIC: COSV99049296;