4-5808197-C-G

Position:

• chr4-5808197-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153717.3(EVC):​c.2562-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,554,030 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (129 hom., cov: 27)
  • Exomes 𝑓: 0.0027 (144 hom.)
• Consequence: EVC NM_153717.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001961
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0400

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

CRMP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-5808197-C-G is Benign according to our data. Variant chr4-5808197-C-G is described in ClinVar as [Benign]. Clinvar id is 349206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.2562-4C>G		splice_region_variant, intron_variant		ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.2562-4C>G		splice_region_variant, intron_variant		1	NM_153717.3	ENSP00000264956.6
CRMP1	ENST00000506216.5	n.1647+17297G>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 3305 AN: 97892 Hom.: 127 Cov.: 27

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0796

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00367

Gnomad EAS AF: 0.000244

Gnomad SAS AF: 0.000327

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000623

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.00627 AC: 1551 AN: 247556 Hom.: 55 AF XY: 0.00453 AC XY: 607 AN XY: 133960

Gnomad AFR exome AF: 0.0831

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000297

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000386

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00265 AC: 3864 AN: 1456044 Hom.: 144 Cov.: 37 AF XY: 0.00238 AC XY: 1720 AN XY: 724166

Gnomad4 AFR exome AF: 0.0892

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00216

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000407

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00722

GnomAD4 genome AF: 0.0340 AC: 3328 AN: 97986 Hom.: 129 Cov.: 27 AF XY: 0.0333 AC XY: 1579 AN XY: 47352

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00367

Gnomad4 EAS AF: 0.000244

Gnomad4 SAS AF: 0.000328

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000623

Gnomad4 OTH AF: 0.0244

Alfa AF: 0.00152 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 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;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.55
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs60082311; hg19: chr4-5809924;