4-5628743-TAA-TAAAA

Position:

• chr4-5628743-TAA-TAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_147127.5(EVC2):​c.1711-10_1711-9insTT variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.151

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 349081.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1711-10_1711-9insTT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1711-10_1711-9insTT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_147127.5	ENSP00000342144	P2
EVC2	ENST00000310917.6	c.1471-10_1471-9insTT		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000311683	A2
EVC2	ENST00000475313.5	c.1471-10_1471-9insTT		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000431981
EVC2	ENST00000509670.1	c.*104-10_*104-9insTT		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000423876

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

GnomAD3 exomes AF: 0.0507 AC: 9529 AN: 187796 Hom.: 89 AF XY: 0.0473 AC XY: 4761 AN XY: 100662

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 SAS exome AF: 0.00756

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

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.0327

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0000836

Gnomad4 SAS exome AF: 0.00748

Gnomad4 FIN exome AF: 0.0654

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0444

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

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.0520

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00902

Gnomad4 FIN AF: 0.0789

Gnomad4 NFE AF: 0.0413

Gnomad4 OTH AF: 0.0693

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2014	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Ellis-van Creveld syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35103377; hg19: chr4-5630470;