4-5628530-C-T

Variant names:

• chr4-5628530-C-T
• rs57185424
• NM_147127.5:c.1886+29G>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.1886+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,112 control chromosomes in the GnomAD database, including 2,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1518 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (1299 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.839
• Publications: 1 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=-0.97).
• BP6: Variant 4-5628530-C-T is Benign according to our data. Variant chr4-5628530-C-T is described in ClinVar as Benign. ClinVar VariationId is 262607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 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.1886+29G>A		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.1646+29G>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.1886+29G>A		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1646+29G>A		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1646+29G>A		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11777 AN: 151994 Hom.: 1510 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0587

GnomAD2 exomes AF: 0.0212 AC: 5329 AN: 251108 AF XY: 0.0156

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.00873 AC: 12750 AN: 1461000 Hom.: 1299 Cov.: 31 AF XY: 0.00765 AC XY: 5560 AN XY: 726844

African (AFR) AF: 0.270 AC: 9035 AN: 33450

American (AMR) AF: 0.0186 AC: 832 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 124 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.000963 AC: 83 AN: 86216

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53352

Middle Eastern (MID) AF: 0.0335 AC: 190 AN: 5680

European-Non Finnish (NFE) AF: 0.00109 AC: 1216 AN: 1111416

Other (OTH) AF: 0.0210 AC: 1265 AN: 60350

GnomAD4 genome AF: 0.0777 AC: 11821 AN: 152112 Hom.: 1518 Cov.: 32 AF XY: 0.0752 AC XY: 5590 AN XY: 74374

African (AFR) AF: 0.265 AC: 10983 AN: 41424

American (AMR) AF: 0.0360 AC: 550 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4812

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68016

Other (OTH) AF: 0.0581 AC: 123 AN: 2116

Alfa AF: 0.0406 Hom.: 242

Bravo AF: 0.0901

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.46
DANN	Benign	0.72
PhyloP100		-0.84
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: rs57185424; hg19: chr4-5630257;