4-5628743-TAA-TAAA

Position:

• chr4-5628743-TAA-TAAA

Variant summary

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

The NM_147127.5(EVC2):​c.1711-10_1711-9insT 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 0.012 (32 hom., cov: 0)
  • Exomes 𝑓: 0.013 (12 hom.)
• Consequence: EVC2 NM_147127.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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-T-TA is Benign according to our data. Variant chr4-5628743-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 1168233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1827 AN: 148626 Hom.: 32 Cov.: 0

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00581

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0109

Gnomad FIN AF: 0.000618

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000330

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0126 AC: 14991 AN: 1193360 Hom.: 12 Cov.: 0 AF XY: 0.0124 AC XY: 7324 AN XY: 592584

Gnomad4 AFR exome AF: 0.0540

Gnomad4 AMR exome AF: 0.00758

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00225

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.00943

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0123 AC: 1828 AN: 148734 Hom.: 32 Cov.: 0 AF XY: 0.0120 AC XY: 872 AN XY: 72486

Gnomad4 AFR AF: 0.0399

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0107

Gnomad4 FIN AF: 0.000618

Gnomad4 NFE AF: 0.000330

Gnomad4 OTH AF: 0.0141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;