rs73198153

Variant names:

• chr4-5622977-A-G
• rs73198153
• NM_147127.5:c.2061T>C
• EVC2 p.Arg687Arg

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_147127.5(EVC2):​c.2061T>C​(p.Arg687Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,613,516 control chromosomes in the GnomAD database, including 5,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1523 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3769 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.708
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• Ellis-van Creveld syndrome

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 4-5622977-A-G is Benign according to our data. Variant chr4-5622977-A-G is described in ClinVar as Benign. ClinVar VariationId is 262609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.708 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.2061T>C	p.Arg687Arg	synonymous	Exon 14 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.1821T>C	p.Arg607Arg	synonymous	Exon 14 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.2061T>C	p.Arg687Arg	synonymous	Exon 14 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1821T>C	p.Arg607Arg	synonymous	Exon 14 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1821T>C		non_coding_transcript_exon	Exon 14 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16588 AN: 152020 Hom.: 1522 Cov.: 33

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0461

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0603

Gnomad OTH AF: 0.0798

GnomAD2 exomes AF: 0.0686 AC: 17071 AN: 248850 AF XY: 0.0692

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.00512

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0608 AC: 88808 AN: 1461378 Hom.: 3769 Cov.: 35 AF XY: 0.0623 AC XY: 45292 AN XY: 727012

African (AFR) AF: 0.249 AC: 8348 AN: 33470

American (AMR) AF: 0.0439 AC: 1964 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 1189 AN: 26128

East Asian (EAS) AF: 0.00325 AC: 129 AN: 39694

South Asian (SAS) AF: 0.113 AC: 9726 AN: 86236

European-Finnish (FIN) AF: 0.0432 AC: 2304 AN: 53342

Middle Eastern (MID) AF: 0.0740 AC: 426 AN: 5760

European-Non Finnish (NFE) AF: 0.0546 AC: 60697 AN: 1111642

Other (OTH) AF: 0.0667 AC: 4025 AN: 60386

GnomAD4 genome AF: 0.109 AC: 16610 AN: 152138 Hom.: 1523 Cov.: 33 AF XY: 0.106 AC XY: 7865 AN XY: 74368

African (AFR) AF: 0.246 AC: 10196 AN: 41486

American (AMR) AF: 0.0582 AC: 890 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3472

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5172

South Asian (SAS) AF: 0.104 AC: 501 AN: 4816

European-Finnish (FIN) AF: 0.0461 AC: 488 AN: 10578

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0603 AC: 4100 AN: 68008

Other (OTH) AF: 0.0818 AC: 173 AN: 2116

Alfa AF: 0.0899 Hom.: 839

Bravo AF: 0.115

Asia WGS AF: 0.0840 AC: 291 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0627

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		-0.71
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs73198153;

hg19: chr4-5624704;