4-5568434-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):c.3557+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,546,346 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 32)
  • Exomes 𝑓: 0.029 (688 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 4-5568434-C-T is Benign according to our data. Variant chr4-5568434-C-T is described in ClinVar as [Benign]. Clinvar id is 195540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5568434-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0204 (3111/152210) while in subpopulation NFE AF= 0.0342 (2327/68014). AF 95% confidence interval is 0.0331. There are 49 homozygotes in gnomad4. There are 1417 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.3557+10G>A		intron_variant		ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.3557+10G>A		intron_variant		1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.3317+10G>A		intron_variant		1		A2
EVC2	ENST00000475313.5	c.3317+10G>A		intron_variant, NMD_transcript_variant		1
EVC2	ENST00000509670.1	c.*1950+10G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3111 AN: 152094 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0184 AC: 2892 AN: 156840 Hom.: 39 AF XY: 0.0183 AC XY: 1546 AN XY: 84650

Gnomad AFR exome AF: 0.00442

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0000809

Gnomad SAS exome AF: 0.00628

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0325

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0289 AC: 40258 AN: 1394136 Hom.: 688 Cov.: 32 AF XY: 0.0281 AC XY: 19390 AN XY: 689080

Gnomad4 AFR exome AF: 0.00476

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.000164

Gnomad4 SAS exome AF: 0.00671

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0340

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0204 AC: 3111 AN: 152210 Hom.: 49 Cov.: 32 AF XY: 0.0190 AC XY: 1417 AN XY: 74414

Gnomad4 AFR AF: 0.00650

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0342

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0120 Hom.: 4

Bravo AF: 0.0196

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ellis-van Creveld syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	1.8
Dann	Benign	0.75

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: rs116218656; hg19: chr4-5570161; COSMIC: COSV60402829;