rs1221185345

Variant names:

• chr4-5708362-TGGGGATCCCG-T
• rs1221185345
• NM_147127.5:c.142_151delCGGGATCCCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_147127.5(EVC2):​c.142_151delCGGGATCCCC​(p.Asp49TrpfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,336,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R48R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: EVC2 NM_147127.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.93
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5708362-TGGGGATCCCG-T is Pathogenic according to our data. Variant chr4-5708362-TGGGGATCCCG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 550552.Status of the report is criteria_provided_single_submitter, 1 stars.

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.142_151delCGGGATCCCC	p.Asp49TrpfsTer9	frameshift	Exon 1 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.-13+457_-13+466delCGGGATCCCC		intron	N/A	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.142_151delCGGGATCCCC	p.Asp49TrpfsTer9	frameshift	Exon 1 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.-13+457_-13+466delCGGGATCCCC		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.-13+457_-13+466delCGGGATCCCC		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 84702 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1336196 Hom.: 0 AF XY: 0.00000304 AC XY: 2 AN XY: 657414

African (AFR) AF: 0.00 AC: 0 AN: 26984

American (AMR) AF: 0.00 AC: 0 AN: 29804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22754

East Asian (EAS) AF: 0.00 AC: 0 AN: 31478

South Asian (SAS) AF: 0.00 AC: 0 AN: 73364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1057776

Other (OTH) AF: 0.00 AC: 0 AN: 55640

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
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
PhyloP100		1.9
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1221185345; hg19: chr4-5710089;