rs60896170

Variant names:

• chr4-5622496-C-T
• rs60896170
• NM_147127.5:c.2501+41G>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.2501+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,598,712 control chromosomes in the GnomAD database, including 3,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2083 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.29
• Publications: 2 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=-1.01).
• BP6: Variant 4-5622496-C-T is Benign according to our data. Variant chr4-5622496-C-T is described in ClinVar as Benign. ClinVar VariationId is 262613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2501+41G>A		intron_variant	Intron 14 of 21	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.2501+41G>A		intron_variant	Intron 14 of 21	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.2261+41G>A		intron_variant	Intron 14 of 21	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.2261+41G>A		intron_variant	Intron 14 of 22	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.*894+41G>A		intron_variant	Intron 15 of 22	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes AF: 0.0972 AC: 14752 AN: 151846 Hom.: 1405 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00872

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0779

GnomAD2 exomes AF: 0.0449 AC: 10223 AN: 227888 AF XY: 0.0400

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.0000596

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0375

GnomAD4 exome AF: 0.0387 AC: 55964 AN: 1446748 Hom.: 2083 Cov.: 31 AF XY: 0.0373 AC XY: 26835 AN XY: 718796

African (AFR) AF: 0.255 AC: 8411 AN: 32994

American (AMR) AF: 0.0313 AC: 1358 AN: 43338

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 636 AN: 25872

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38844

South Asian (SAS) AF: 0.00726 AC: 609 AN: 83850

European-Finnish (FIN) AF: 0.0671 AC: 3531 AN: 52646

Middle Eastern (MID) AF: 0.0636 AC: 366 AN: 5754

European-Non Finnish (NFE) AF: 0.0349 AC: 38464 AN: 1103618

Other (OTH) AF: 0.0432 AC: 2584 AN: 59832

GnomAD4 genome AF: 0.0972 AC: 14766 AN: 151964 Hom.: 1408 Cov.: 32 AF XY: 0.0972 AC XY: 7219 AN XY: 74282

African (AFR) AF: 0.245 AC: 10136 AN: 41398

American (AMR) AF: 0.0508 AC: 777 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00873 AC: 42 AN: 4810

European-Finnish (FIN) AF: 0.0784 AC: 830 AN: 10584

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2696 AN: 67954

Other (OTH) AF: 0.0766 AC: 161 AN: 2102

Alfa AF: 0.0670 Hom.: 145

Bravo AF: 0.102

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.077
DANN	Benign	0.51
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs60896170; hg19: chr4-5624223;