NM_147127.5:c.194_198dupGGCGG

Variant names:

• chr4-5708315-T-TCCGCC
• rs992326794
• NM_147127.5:c.194_198dupGGCGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_147127.5(EVC2):​c.194_198dupGGCGG​(p.Ser67GlyfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,502 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. R66R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: EVC2 NM_147127.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.243
• 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 18 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 4-5708315-T-TCCGCC is Pathogenic according to our data. Variant chr4-5708315-T-TCCGCC is described in ClinVar as Pathogenic. ClinVar VariationId is 556341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.194_198dupGGCGG	p.Ser67GlyfsTer17	frameshift	Exon 1 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.-13+509_-13+513dupGGCGG		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.194_198dupGGCGG	p.Ser67GlyfsTer17	frameshift	Exon 1 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.-13+509_-13+513dupGGCGG		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.-13+509_-13+513dupGGCGG		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000305 AC: 4 AN: 1309508 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 642438

African (AFR) AF: 0.00 AC: 0 AN: 26418

American (AMR) AF: 0.00 AC: 0 AN: 25848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21884

East Asian (EAS) AF: 0.00 AC: 0 AN: 29810

South Asian (SAS) AF: 0.00 AC: 0 AN: 69330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.00000383 AC: 4 AN: 1043158

Other (OTH) AF: 0.00 AC: 0 AN: 54450

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149994 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73228

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000247 AC: 1 AN: 40566

American (AMR) AF: 0.00 AC: 0 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4980

South Asian (SAS) AF: 0.00 AC: 0 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67440

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Ellis-van Creveld syndrome (3)
1	-	-	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs992326794; hg19: chr4-5710042;