rs2287576

Variant names:

• chr4-5562464-A-T
• rs2287576
• NM_147127.5:c.*384T>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.*384T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 1,060,184 control chromosomes in the GnomAD database, including 313,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33577 hom., cov: 33)
  • Exomes 𝑓: 0.78 (280062 hom.)
• Consequence: EVC2 NM_147127.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.388
• Publications: 3 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 (BayesDel_noAF=-0.94).
• BP6: Variant 4-5562464-A-T is Benign according to our data. Variant chr4-5562464-A-T is described in ClinVar as Benign. ClinVar VariationId is 348976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.788 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.*384T>A		3_prime_UTR	Exon 22 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.*384T>A		3_prime_UTR	Exon 22 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.*384T>A		3_prime_UTR	Exon 22 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.*384T>A		3_prime_UTR	Exon 22 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.3419+2794T>A		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96897 AN: 151994 Hom.: 33556 Cov.: 33

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.780 AC: 708203 AN: 908072 Hom.: 280062 Cov.: 20 AF XY: 0.780 AC XY: 330754 AN XY: 423942

African (AFR) AF: 0.330 AC: 6084 AN: 18422

American (AMR) AF: 0.638 AC: 3260 AN: 5110

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 5357 AN: 7226

East Asian (EAS) AF: 0.277 AC: 2268 AN: 8198

South Asian (SAS) AF: 0.730 AC: 18954 AN: 25970

European-Finnish (FIN) AF: 0.727 AC: 3498 AN: 4814

Middle Eastern (MID) AF: 0.692 AC: 1318 AN: 1906

European-Non Finnish (NFE) AF: 0.800 AC: 643986 AN: 804738

Other (OTH) AF: 0.741 AC: 23478 AN: 31688

GnomAD4 genome AF: 0.637 AC: 96953 AN: 152112 Hom.: 33577 Cov.: 33 AF XY: 0.631 AC XY: 46892 AN XY: 74360

African (AFR) AF: 0.374 AC: 15516 AN: 41484

American (AMR) AF: 0.652 AC: 9953 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2572 AN: 3472

East Asian (EAS) AF: 0.311 AC: 1605 AN: 5164

South Asian (SAS) AF: 0.700 AC: 3377 AN: 4822

European-Finnish (FIN) AF: 0.719 AC: 7606 AN: 10584

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 53960 AN: 67990

Other (OTH) AF: 0.658 AC: 1391 AN: 2114

Alfa AF: 0.696 Hom.: 4771

Bravo AF: 0.614

Asia WGS AF: 0.531 AC: 1847 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.038
DANN	Benign	0.085
PhyloP100		-0.39
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: rs2287576; hg19: chr4-5564191;