rs138972736

chr4-5640786-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):c.1198A>G(p.Thr400Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,186 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (15 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.38

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 (MetaRNN=0.005721569).
• BP6: Variant 4-5640786-T-C is Benign according to our data. Variant chr4-5640786-T-C is described in ClinVar as [Benign]. Clinvar id is 349089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00612 (932/152302) while in subpopulation AFR AF= 0.0214 (888/41548). AF 95% confidence interval is 0.0202. There are 14 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.1198A>G	p.Thr400Ala	missense_variant	10/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.1198A>G	p.Thr400Ala	missense_variant	10/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.958A>G	p.Thr320Ala	missense_variant	10/22	1		A2
EVC2	ENST00000475313.5	c.958A>G	p.Thr320Ala	missense_variant, NMD_transcript_variant	10/23	1
EVC2	ENST00000509670.1	c.958A>G	p.Thr320Ala	missense_variant, NMD_transcript_variant	11/23	1

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 932 AN: 152184 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00163 AC: 409 AN: 251346 Hom.: 11 AF XY: 0.00124 AC XY: 169 AN XY: 135840

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000670 AC: 979 AN: 1461884 Hom.: 15 Cov.: 34 AF XY: 0.000578 AC XY: 420 AN XY: 727238

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00612 AC: 932 AN: 152302 Hom.: 14 Cov.: 32 AF XY: 0.00572 AC XY: 426 AN XY: 74478

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00118 Hom.: 3

Bravo AF: 0.00712

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2017

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 Benign:1

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.23
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.050	T;T
Polyphen		0.83	P;.
Vest4		0.11
MVP		0.75
MPC		0.026
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.071
gMVP		0.13

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: rs138972736; hg19: chr4-5642513;