rs544397395

chr4-5708392-G-T

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.122C>A(p.Pro41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,496,282 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (22 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.448

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=0.0061277747).
• BP6: Variant 4-5708392-G-T is Benign according to our data. Variant chr4-5708392-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193503.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1}. Variant chr4-5708392-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00281 (428/152100) while in subpopulation NFE AF= 0.00453 (308/67948). AF 95% confidence interval is 0.00412. There are 2 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.122C>A	p.Pro41His	missense_variant	1/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.122C>A	p.Pro41His	missense_variant	1/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.-13+437C>A		intron_variant		1		A2
EVC2	ENST00000475313.5	c.-13+437C>A		intron_variant, NMD_transcript_variant		1
EVC2	ENST00000509670.1	c.-106-252C>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 428 AN: 151984 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00361 AC: 331 AN: 91778 Hom.: 1 AF XY: 0.00352 AC XY: 182 AN XY: 51648

Gnomad AFR exome AF: 0.000659

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000588

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00484 AC: 6506 AN: 1344182 Hom.: 22 Cov.: 30 AF XY: 0.00470 AC XY: 3115 AN XY: 662254

Gnomad4 AFR exome AF: 0.000698

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000660

Gnomad4 NFE exome AF: 0.00540

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152100 Hom.: 2 Cov.: 32 AF XY: 0.00248 AC XY: 184 AN XY: 74342

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00459 Hom.: 0

Bravo AF: 0.00280

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00441 AC: 17

ExAC AF: 0.00155 AC: 57

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Ellis-van Creveld syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.14
MVP		0.77
MPC		0.11
ClinPred		0.033	T
GERP RS		1.9
Varity_R		0.065
gMVP		0.15

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: rs544397395; hg19: chr4-5710119; COSMIC: COSV53832620; COSMIC: COSV53832620;