4-5628743-T-TAA

Variant names:

• chr4-5628743-T-TAA
• rs35103377
• NM_147127.5:c.1711-11_1711-10dupTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_147127.5(EVC2):​c.1711-11_1711-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.091 (1107 hom., cov: 0)
  • Exomes 𝑓: 0.040 (318 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.151
• 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 -9 ACMG points.

• BP6: Variant 4-5628743-T-TAA is Benign according to our data. Variant chr4-5628743-T-TAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 349081.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 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.1711-11_1711-10dupTT		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.1471-11_1471-10dupTT		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.1711-10_1711-9insTT		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1471-10_1471-9insTT		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1471-10_1471-9insTT		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0912 AC: 13554 AN: 148592 Hom.: 1101 Cov.: 0

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0629

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00878

Gnomad FIN AF: 0.0789

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0706

GnomAD2 exomes AF: 0.0507 AC: 9529 AN: 187796 AF XY: 0.0473

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.0000624

Gnomad FIN exome AF: 0.0809

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0404 AC: 51202 AN: 1268394 Hom.: 318 Cov.: 0 AF XY: 0.0393 AC XY: 24823 AN XY: 631496

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.198 AC: 6242 AN: 31480

American (AMR) AF: 0.0327 AC: 1303 AN: 39830

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 565 AN: 22372

East Asian (EAS) AF: 0.0000836 AC: 3 AN: 35880

South Asian (SAS) AF: 0.00748 AC: 558 AN: 74562

European-Finnish (FIN) AF: 0.0654 AC: 3003 AN: 45904

Middle Eastern (MID) AF: 0.0645 AC: 325 AN: 5042

European-Non Finnish (NFE) AF: 0.0384 AC: 36873 AN: 960798

Other (OTH) AF: 0.0444 AC: 2330 AN: 52526

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0913 AC: 13577 AN: 148700 Hom.: 1107 Cov.: 0 AF XY: 0.0919 AC XY: 6659 AN XY: 72466

African (AFR) AF: 0.219 AC: 8939 AN: 40908

American (AMR) AF: 0.0520 AC: 780 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 72 AN: 3412

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5096

South Asian (SAS) AF: 0.00902 AC: 42 AN: 4654

European-Finnish (FIN) AF: 0.0789 AC: 765 AN: 9698

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0413 AC: 2758 AN: 66716

Other (OTH) AF: 0.0693 AC: 142 AN: 2048

Alfa AF: 0.0357 Hom.: 399

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (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
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35103377; hg19: chr4-5630470;