NM_147127.5:c.2046+5A>G

Variant names:

• chr4-5625744-T-C
• rs6850875
• NM_147127.5:c.2046+5A>G

Variant summary

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

The NM_147127.5(EVC2):​c.2046+5A>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 0.0123 in 1,614,128 control chromosomes in the GnomAD database, including 1,875 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 0.064 (946 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (929 hom.)
• Consequence: EVC2 NM_147127.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004271
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.824

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=-0.92).
• BP6: Variant 4-5625744-T-C is Benign according to our data. Variant chr4-5625744-T-C is described in ClinVar as [Benign]. Clinvar id is 262608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5625744-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5	c.2046+5A>G		splice_region_variant, intron_variant	Intron 13 of 21	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.2046+5A>G		splice_region_variant, intron_variant	Intron 13 of 21	1	NM_147127.5	ENSP00000342144.5
EVC2	ENST00000310917.6	c.1806+5A>G		splice_region_variant, intron_variant	Intron 13 of 21	1		ENSP00000311683.2
EVC2	ENST00000475313.5	n.1806+5A>G		splice_region_variant, intron_variant	Intron 13 of 22	1		ENSP00000431981.1
EVC2	ENST00000509670.1	n.*439+5A>G		splice_region_variant, intron_variant	Intron 14 of 22	1		ENSP00000423876.1

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9656 AN: 152174 Hom.: 947 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0293

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0458

GnomAD3 exomes AF: 0.0174 AC: 4365 AN: 251350 Hom.: 398 AF XY: 0.0131 AC XY: 1774 AN XY: 135866

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00693 AC: 10134 AN: 1461836 Hom.: 929 Cov.: 32 AF XY: 0.00617 AC XY: 4487 AN XY: 727218

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000616

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0636 AC: 9685 AN: 152292 Hom.: 946 Cov.: 32 AF XY: 0.0608 AC XY: 4527 AN XY: 74484

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.0458

Alfa AF: 0.00937 Hom.: 282

Bravo AF: 0.0718

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 09, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ellis-van Creveld syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.067
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.010
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: rs6850875; hg19: chr4-5627471;