chr4-5642651-T-A

Variant names:

• chr4-5642651-T-A
• rs6446384
• NM_147127.5:c.1146-1813A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_147127.5(EVC2):​c.1146-1813A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 152,052 control chromosomes in the GnomAD database, including 36,365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (36365 hom., cov: 32)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.84
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 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.1146-1813A>T		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.906-1813A>T		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.1146-1813A>T		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.906-1813A>T		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.906-1813A>T		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104149 AN: 151934 Hom.: 36326 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.683

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.686 AC: 104237 AN: 152052 Hom.: 36365 Cov.: 32 AF XY: 0.682 AC XY: 50695 AN XY: 74314

African (AFR) AF: 0.821 AC: 34044 AN: 41488

American (AMR) AF: 0.623 AC: 9526 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2316 AN: 3466

East Asian (EAS) AF: 0.601 AC: 3094 AN: 5148

South Asian (SAS) AF: 0.558 AC: 2681 AN: 4804

European-Finnish (FIN) AF: 0.649 AC: 6856 AN: 10558

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43624 AN: 67990

Other (OTH) AF: 0.676 AC: 1429 AN: 2114

Alfa AF: 0.679 Hom.: 4408

Bravo AF: 0.694

Asia WGS AF: 0.594 AC: 2063 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.084
DANN	Benign	0.31
PhyloP100		-2.8
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: rs6446384; hg19: chr4-5644378;