rs58869180

Positions:

• chr4-5628754-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147127.5(EVC2):​c.1711-20T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,484,598 control chromosomes in the GnomAD database, including 2,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (1166 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (1036 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.87

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-5628754-A-C is Benign according to our data. Variant chr4-5628754-A-C is described in ClinVar as [Benign]. Clinvar id is 262606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1711-20T>G		intron_variant		ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1711-20T>G		intron_variant		1	NM_147127.5	ENSP00000342144	P2
EVC2	ENST00000310917.6	c.1471-20T>G		intron_variant		1		ENSP00000311683	A2
EVC2	ENST00000475313.5	c.1471-20T>G		intron_variant, NMD_transcript_variant		1		ENSP00000431981
EVC2	ENST00000509670.1	c.*104-20T>G		intron_variant, NMD_transcript_variant		1		ENSP00000423876

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10353 AN: 150786 Hom.: 1163 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0186 AC: 4607 AN: 247834 Hom.: 452 AF XY: 0.0139 AC XY: 1861 AN XY: 134310

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.00499

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000802

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.00848 AC: 11315 AN: 1333696 Hom.: 1036 Cov.: 30 AF XY: 0.00742 AC XY: 4958 AN XY: 668028

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000908

Gnomad4 FIN exome AF: 0.0000585

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0688 AC: 10383 AN: 150902 Hom.: 1166 Cov.: 32 AF XY: 0.0666 AC XY: 4912 AN XY: 73710

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.0335

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.0474

Alfa AF: 0.0376 Hom.: 96

Bravo AF: 0.0796

Asia WGS AF: 0.0210 AC: 73 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2016	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. -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.022
DANN	Benign	0.53

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: rs58869180; hg19: chr4-5630481;