rs557830930

Positions:

• chr4-5708422-A-G

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.92T>C​(p.Leu31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,503,748 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L31L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -1.13

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=0.003951043).
• BP6: Variant 4-5708422-A-G is Benign according to our data. Variant chr4-5708422-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285109.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000901 (137/152054) while in subpopulation AMR AF= 0.00471 (72/15302). AF 95% confidence interval is 0.00383. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.92T>C	p.Leu31Pro	missense_variant	1/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.92T>C	p.Leu31Pro	missense_variant	1/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.-13+407T>C		intron_variant		1		A2
EVC2	ENST00000475313.5	c.-13+407T>C		intron_variant, NMD_transcript_variant		1
EVC2	ENST00000509670.1	c.-106-282T>C		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 137 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00129 AC: 127 AN: 98786 Hom.: 1 AF XY: 0.00114 AC XY: 63 AN XY: 55316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000758

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.000601 AC: 813 AN: 1351694 Hom.: 4 Cov.: 30 AF XY: 0.000591 AC XY: 394 AN XY: 666358

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00583

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000599

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.000901 AC: 137 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000780 AC XY: 58 AN XY: 74318

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00121

ExAC AF: 0.000694 AC: 22

Asia WGS AF: 0.000868 AC: 3 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2015	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.92T>C (p.L31P) alteration is located in exon 1 (coding exon 1) of the EVC2 gene. This alteration results from a T to C substitution at nucleotide position 92, causing the leucine (L) at amino acid position 31 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Ellis-van Creveld syndrome Benign:1

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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

EVC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 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). -

Curry-Hall syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.31
MutPred		0.22		Loss of catalytic residue at L31 (P = 0.0331);
MVP		0.45
MPC		0.024
ClinPred		0.028	T
GERP RS		-0.73
Varity_R		0.093
gMVP		0.18

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: rs557830930; hg19: chr4-5710149;