4-5628743-TAA-TA

Position:

• chr4-5628743-TAA-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_147127.5(EVC2):​c.1711-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8930 hom., cov: 0)
  • Exomes 𝑓: 0.32 (44029 hom.)
• Consequence: EVC2 NM_147127.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 -16 ACMG points.

• BP6: Variant 4-5628743-TA-T is Benign according to our data. Variant chr4-5628743-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1168070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5628743-TA-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.333 AC: 49509 AN: 148518 Hom.: 8910 Cov.: 0

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.309

GnomAD3 exomes AF: 0.409 AC: 76853 AN: 187796 Hom.: 12124 AF XY: 0.401 AC XY: 40329 AN XY: 100662

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.655

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.316 AC: 378436 AN: 1199090 Hom.: 44029 Cov.: 0 AF XY: 0.315 AC XY: 187736 AN XY: 595598

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.459

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.324

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.334 AC: 49569 AN: 148626 Hom.: 8930 Cov.: 0 AF XY: 0.337 AC XY: 24433 AN XY: 72424

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.615

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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;C0457013:Curry-Hall syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs35103377; hg19: chr4-5630470;