NM_147127.5:c.2095A>G

Variant names:

• chr4-5622943-T-C
• rs730469
• NM_147127.5:c.2095A>G

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.2095A>G​(p.Thr699Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,758 control chromosomes in the GnomAD database, including 94,610 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. T699M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.45 (18957 hom., cov: 32)
  • Exomes 𝑓: 0.31 (75653 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.54
• Publications: 34 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=1.0240383E-6).
• BP6: Variant 4-5622943-T-C is Benign according to our data. Variant chr4-5622943-T-C is described in ClinVar as Benign. ClinVar VariationId is 262610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 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.2095A>G	p.Thr699Ala	missense	Exon 14 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.1855A>G	p.Thr619Ala	missense	Exon 14 of 22	NP_001159608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.2095A>G	p.Thr699Ala	missense	Exon 14 of 22	ENSP00000342144.5
	EVC2	ENST00000310917.6	TSL:1	c.1855A>G	p.Thr619Ala	missense	Exon 14 of 22	ENSP00000311683.2
	EVC2	ENST00000475313.5	TSL:1	n.1855A>G		non_coding_transcript_exon	Exon 14 of 23	ENSP00000431981.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67848 AN: 151906 Hom.: 18912 Cov.: 32

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.394

GnomAD2 exomes AF: 0.366 AC: 91740 AN: 250438 AF XY: 0.351

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.633

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.305 AC: 445835 AN: 1461732 Hom.: 75653 Cov.: 66 AF XY: 0.303 AC XY: 219983 AN XY: 727156

African (AFR) AF: 0.807 AC: 27026 AN: 33476

American (AMR) AF: 0.419 AC: 18754 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6912 AN: 26136

East Asian (EAS) AF: 0.609 AC: 24170 AN: 39698

South Asian (SAS) AF: 0.285 AC: 24550 AN: 86250

European-Finnish (FIN) AF: 0.339 AC: 18084 AN: 53372

Middle Eastern (MID) AF: 0.321 AC: 1853 AN: 5764

European-Non Finnish (NFE) AF: 0.274 AC: 304628 AN: 1111930

Other (OTH) AF: 0.329 AC: 19858 AN: 60386

GnomAD4 genome AF: 0.447 AC: 67942 AN: 152026 Hom.: 18957 Cov.: 32 AF XY: 0.450 AC XY: 33415 AN XY: 74300

African (AFR) AF: 0.788 AC: 32685 AN: 41486

American (AMR) AF: 0.408 AC: 6228 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 921 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3149 AN: 5160

South Asian (SAS) AF: 0.300 AC: 1445 AN: 4820

European-Finnish (FIN) AF: 0.351 AC: 3704 AN: 10562

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18681 AN: 67944

Other (OTH) AF: 0.389 AC: 821 AN: 2112

Alfa AF: 0.336 Hom.: 34770

Bravo AF: 0.472

TwinsUK AF: 0.265 AC: 983

ALSPAC AF: 0.273 AC: 1053

ESP6500AA AF: 0.773 AC: 3407

ESP6500EA AF: 0.278 AC: 2393

ExAC AF: 0.369 AC: 44836

Asia WGS AF: 0.478 AC: 1661 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.283

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ellis-van Creveld 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	0.058
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.3
DANN	Benign	0.15
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.020
ClinPred		0.00073	T
GERP RS		0.37
Varity_R		0.022
gMVP		0.039
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: rs730469; hg19: chr4-5624670; COSMIC: COSV60389754;