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, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.519+15G>A		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.279+15G>A		intron	N/A	NP_001159608.1	Q86UK5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.519+15G>A		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.279+15G>A		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.279+15G>A		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;