rs4689261

Variant names:

• chr4-5575608-G-A
• rs4689261
• NM_147127.5:c.3272+632C>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.3272+632C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 152,078 control chromosomes in the GnomAD database, including 18,657 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 0.47 (18657 hom., cov: 33)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710
• 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, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.3272+632C>T		intron_variant	Intron 18 of 21	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.3272+632C>T		intron_variant	Intron 18 of 21	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.3032+632C>T		intron_variant	Intron 18 of 21	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.3032+632C>T		intron_variant	Intron 18 of 22	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.*1665+632C>T		intron_variant	Intron 19 of 22	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71471 AN: 151958 Hom.: 18592 Cov.: 33

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.471 AC: 71595 AN: 152078 Hom.: 18657 Cov.: 33 AF XY: 0.480 AC XY: 35681 AN XY: 74334

African (AFR) AF: 0.664 AC: 27536 AN: 41464

American (AMR) AF: 0.447 AC: 6831 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1203 AN: 3472

East Asian (EAS) AF: 0.858 AC: 4441 AN: 5174

South Asian (SAS) AF: 0.542 AC: 2618 AN: 4826

European-Finnish (FIN) AF: 0.430 AC: 4543 AN: 10558

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23106 AN: 67976

Other (OTH) AF: 0.454 AC: 957 AN: 2108

Alfa AF: 0.456 Hom.: 5431

Bravo AF: 0.483

Asia WGS AF: 0.723 AC: 2512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.29
DANN	Benign	0.75
PhyloP100		-0.71
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: rs4689261; hg19: chr4-5577335;