rs17688121

Positions:

• chr4-5691250-C-T

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.519+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,604,412 control chromosomes in the GnomAD database, including 18,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1187 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17065 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0110

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=-0.85).
• BP6: Variant 4-5691250-C-T is Benign according to our data. Variant chr4-5691250-C-T is described in ClinVar as [Benign]. Clinvar id is 262617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.519+15G>A		intron_variant		ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.519+15G>A		intron_variant		1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.279+15G>A		intron_variant		1		A2
EVC2	ENST00000475313.5	c.279+15G>A		intron_variant, NMD_transcript_variant		1
EVC2	ENST00000509670.1	c.279+15G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16952 AN: 151992 Hom.: 1188 Cov.: 33

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0996

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.125 AC: 31462 AN: 251026 Hom.: 2348 AF XY: 0.132 AC XY: 17887 AN XY: 135722

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.0754

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.147 AC: 214116 AN: 1452302 Hom.: 17065 Cov.: 29 AF XY: 0.149 AC XY: 107387 AN XY: 722938

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.0812

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.000505

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.111 AC: 16949 AN: 152110 Hom.: 1187 Cov.: 33 AF XY: 0.108 AC XY: 8050 AN XY: 74336

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.0992

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.131

Alfa AF: 0.145 Hom.: 971

Bravo AF: 0.105

Asia WGS AF: 0.0530 AC: 184 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

- -

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. -

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	-0.85
CADD	Benign	7.9
DANN	Benign	0.27

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: rs17688121; hg19: chr4-5692977;