chr4-5625744-T-C

Variant names:

• chr4-5625744-T-C
• rs6850875
• NM_147127.5:c.2046+5A>G

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.2046+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,128 control chromosomes in the GnomAD database, including 1,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (946 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (929 hom.)
• Consequence: EVC2 NM_147127.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004271
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.824
• 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=-0.92).
• BP6: Variant 4-5625744-T-C is Benign according to our data. Variant chr4-5625744-T-C is described in ClinVar as Benign. ClinVar VariationId is 262608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 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.2046+5A>G		splice_region intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.1806+5A>G		splice_region 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.2046+5A>G		splice_region intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1806+5A>G		splice_region intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1806+5A>G		splice_region intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9656 AN: 152174 Hom.: 947 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0293

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0458

GnomAD2 exomes AF: 0.0174 AC: 4365 AN: 251350 AF XY: 0.0131

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00693 AC: 10134 AN: 1461836 Hom.: 929 Cov.: 32 AF XY: 0.00617 AC XY: 4487 AN XY: 727218

African (AFR) AF: 0.229 AC: 7670 AN: 33474

American (AMR) AF: 0.0148 AC: 660 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.0140 AC: 81 AN: 5766

European-Non Finnish (NFE) AF: 0.000616 AC: 685 AN: 1112004

Other (OTH) AF: 0.0154 AC: 933 AN: 60396

GnomAD4 genome AF: 0.0636 AC: 9685 AN: 152292 Hom.: 946 Cov.: 32 AF XY: 0.0608 AC XY: 4527 AN XY: 74484

African (AFR) AF: 0.218 AC: 9043 AN: 41538

American (AMR) AF: 0.0292 AC: 447 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68028

Other (OTH) AF: 0.0458 AC: 97 AN: 2116

Alfa AF: 0.0235 Hom.: 1032

Bravo AF: 0.0718

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00225

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	-0.92
CADD	Benign	0.067
DANN	Benign	0.62
PhyloP100		-0.82
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.010
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: rs6850875; hg19: chr4-5627471;