4-5562464-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_147127.5(EVC2):c.*384T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 1,060,184 control chromosomes in the GnomAD database, including 313,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.64 (33577 hom., cov: 33)
  • Exomes 𝑓: 0.78 (280062 hom.)
• Consequence: EVC2 NM_147127.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.388

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-5562464-A-T is Benign according to our data. Variant chr4-5562464-A-T is described in ClinVar as [Benign]. Clinvar id is 348976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.*384T>A		3_prime_UTR_variant	22/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.*384T>A		3_prime_UTR_variant	22/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.*384T>A		3_prime_UTR_variant	22/22	1		A2
EVC2	ENST00000475313.5	c.3419+2794T>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96897 AN: 151994 Hom.: 33556 Cov.: 33

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.780 AC: 708203 AN: 908072 Hom.: 280062 Cov.: 20 AF XY: 0.780 AC XY: 330754 AN XY: 423942

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.741

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.730

Gnomad4 FIN exome AF: 0.727

Gnomad4 NFE exome AF: 0.800

Gnomad4 OTH exome AF: 0.741

GnomAD4 genome AF: 0.637 AC: 96953 AN: 152112 Hom.: 33577 Cov.: 33 AF XY: 0.631 AC XY: 46892 AN XY: 74360

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.741

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.700

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.794

Gnomad4 OTH AF: 0.658

Alfa AF: 0.696 Hom.: 4771

Bravo AF: 0.614

Asia WGS AF: 0.531 AC: 1847 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ellis-van Creveld syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.038
Dann	Benign	0.085

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

Publications

LitVar

Other links and lift over

dbSNP: rs2287576; hg19: chr4-5564191;