rs4689273

Variant names:

• chr4-5663474-G-A
• rs4689273
• NM_147127.5:c.1006-228C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_147127.5(EVC2):​c.1006-228C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,088 control chromosomes in the GnomAD database, including 10,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (10051 hom., cov: 33)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.293
• 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Ellis-van Creveld syndrome

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-5663474-G-A is Benign according to our data. Variant chr4-5663474-G-A is described in ClinVar as Benign. ClinVar VariationId is 671282.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1006-228C>T		intron_variant	Intron 8 of 21	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1006-228C>T		intron_variant	Intron 8 of 21	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.766-228C>T		intron_variant	Intron 8 of 21	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.766-228C>T		intron_variant	Intron 8 of 22	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.766-228C>T		intron_variant	Intron 9 of 22	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53078 AN: 151970 Hom.: 10050 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.370

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

GnomAD4 genome AF: 0.349 AC: 53084 AN: 152088 Hom.: 10051 Cov.: 33 AF XY: 0.351 AC XY: 26077 AN XY: 74350

African (AFR) AF: 0.191 AC: 7904 AN: 41490

American (AMR) AF: 0.394 AC: 6024 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1325 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2485 AN: 5168

South Asian (SAS) AF: 0.354 AC: 1705 AN: 4816

European-Finnish (FIN) AF: 0.436 AC: 4613 AN: 10572

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.411 AC: 27945 AN: 67962

Other (OTH) AF: 0.365 AC: 772 AN: 2114

Alfa AF: 0.389 Hom.: 38006

Bravo AF: 0.344

Asia WGS AF: 0.378 AC: 1312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.53
DANN	Benign	0.27
PhyloP100		-0.29
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: rs4689273; hg19: chr4-5665201;