rs141287105

chr4-5640620-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_147127.5(EVC2):c.1364C>G(p.Thr455Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00572 in 1,614,032 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (28 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 4.61

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009402782).
• BP6: Variant 4-5640620-G-C is Benign according to our data. Variant chr4-5640620-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193762.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=3}. Variant chr4-5640620-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00396 (602/152158) while in subpopulation NFE AF= 0.00723 (492/68022). AF 95% confidence interval is 0.0067. There are 1 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.1364C>G	p.Thr455Arg	missense_variant	10/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.1364C>G	p.Thr455Arg	missense_variant	10/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.1124C>G	p.Thr375Arg	missense_variant	10/22	1		A2
EVC2	ENST00000475313.5	c.1124C>G	p.Thr375Arg	missense_variant, NMD_transcript_variant	10/23	1
EVC2	ENST00000509670.1	c.1124C>G	p.Thr375Arg	missense_variant, NMD_transcript_variant	11/23	1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152040 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00367 AC: 923 AN: 251464 Hom.: 4 AF XY: 0.00373 AC XY: 507 AN XY: 135904

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.00645

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00590 AC: 8627 AN: 1461874 Hom.: 28 Cov.: 34 AF XY: 0.00575 AC XY: 4179 AN XY: 727232

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00391

Gnomad4 NFE exome AF: 0.00713

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.00396 AC: 602 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.00370 AC XY: 275 AN XY: 74376

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.00723

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00621 Hom.: 3

Bravo AF: 0.00334

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00396 AC: 481

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	EVC2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	This variant is associated with the following publications: (PMID: 32859249) -

Ellis-van Creveld syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation was found once in our laboratory in trans with another variant in a 3-year-old male with ectodermal dysplasia. Heterozygotes would be expected to be asymptomatic carriers. -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 11, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

EVC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0094	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.98	D;.
Vest4		0.55
MVP		0.87
MPC		0.14
ClinPred		0.023	T
GERP RS		3.3
Varity_R		0.18
gMVP		0.45

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: rs141287105; hg19: chr4-5642347;