4-5568434-C-T

Variant names:

• chr4-5568434-C-T
• rs116218656
• NM_147127.5:c.3557+10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):​c.3557+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,546,346 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 32)
  • Exomes 𝑓: 0.029 (688 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.90
• 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 4-5568434-C-T is Benign according to our data. Variant chr4-5568434-C-T is described in ClinVar as Benign. ClinVar VariationId is 195540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0204 (3111/152210) while in subpopulation NFE AF = 0.0342 (2327/68014). AF 95% confidence interval is 0.0331. There are 49 homozygotes in GnomAd4. There are 1417 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR,AD gene

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.3557+10G>A		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.3317+10G>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.3557+10G>A		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.3317+10G>A		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.3317+10G>A		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3111 AN: 152094 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0184 AC: 2892 AN: 156840 AF XY: 0.0183

Gnomad AFR exome AF: 0.00442

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0000809

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0325

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0289 AC: 40258 AN: 1394136 Hom.: 688 Cov.: 32 AF XY: 0.0281 AC XY: 19390 AN XY: 689080

African (AFR) AF: 0.00476 AC: 153 AN: 32146

American (AMR) AF: 0.0116 AC: 432 AN: 37188

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 296 AN: 25206

East Asian (EAS) AF: 0.000164 AC: 6 AN: 36546

South Asian (SAS) AF: 0.00671 AC: 534 AN: 79574

European-Finnish (FIN) AF: 0.0198 AC: 729 AN: 36874

Middle Eastern (MID) AF: 0.00467 AC: 19 AN: 4072

European-Non Finnish (NFE) AF: 0.0340 AC: 36821 AN: 1084386

Other (OTH) AF: 0.0218 AC: 1268 AN: 58144

GnomAD4 genome AF: 0.0204 AC: 3111 AN: 152210 Hom.: 49 Cov.: 32 AF XY: 0.0190 AC XY: 1417 AN XY: 74414

African (AFR) AF: 0.00650 AC: 270 AN: 41528

American (AMR) AF: 0.0159 AC: 243 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0342 AC: 2327 AN: 68014

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0120 Hom.: 4

Bravo AF: 0.0196

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		-1.9
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: rs116218656; hg19: chr4-5570161; COSMIC: COSV60402829;