rs17688121

Variant names:

• chr4-5691250-C-T
• rs17688121
• NM_147127.5:c.519+15G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 VariationId 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 rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.519+15G>A		intron_variant	Intron 4 of 21	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.519+15G>A		intron_variant	Intron 4 of 21	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.279+15G>A		intron_variant	Intron 4 of 21	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.279+15G>A		intron_variant	Intron 4 of 22	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.279+15G>A		intron_variant	Intron 5 of 22	1		ENSP00000423876.1

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

GnomAD2 exomes AF: 0.125 AC: 31462 AN: 251026 AF XY: 0.132

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 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

African (AFR) AF: 0.0280 AC: 936 AN: 33400

American (AMR) AF: 0.0812 AC: 3629 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5378 AN: 26044

East Asian (EAS) AF: 0.000505 AC: 20 AN: 39588

South Asian (SAS) AF: 0.132 AC: 11332 AN: 85984

European-Finnish (FIN) AF: 0.136 AC: 7262 AN: 53382

Middle Eastern (MID) AF: 0.166 AC: 951 AN: 5728

European-Non Finnish (NFE) AF: 0.160 AC: 176023 AN: 1103420

Other (OTH) AF: 0.143 AC: 8585 AN: 60080

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

African (AFR) AF: 0.0317 AC: 1318 AN: 41520

American (AMR) AF: 0.0992 AC: 1517 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 682 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5178

South Asian (SAS) AF: 0.122 AC: 588 AN: 4818

European-Finnish (FIN) AF: 0.136 AC: 1436 AN: 10548

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10934 AN: 67970

Other (OTH) AF: 0.131 AC: 275 AN: 2106

Alfa AF: 0.141 Hom.: 1313

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

Apr 07, 2016

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ellis-van Creveld syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.9
DANN	Benign	0.27
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs17688121; hg19: chr4-5692977;