4-5640789-G-C

Position:

• chr4-5640789-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_147127.5(EVC2):​c.1195C>G​(p.Arg399Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1195C>G	p.Arg399Gly	missense_variant	10/22	ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1195C>G	p.Arg399Gly	missense_variant	10/22	1	NM_147127.5	ENSP00000342144	P2
EVC2	ENST00000310917.6	c.955C>G	p.Arg319Gly	missense_variant	10/22	1		ENSP00000311683	A2
EVC2	ENST00000475313.5	c.955C>G	p.Arg319Gly	missense_variant, NMD_transcript_variant	10/23	1		ENSP00000431981
EVC2	ENST00000509670.1	c.955C>G	p.Arg319Gly	missense_variant, NMD_transcript_variant	11/23	1		ENSP00000423876

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.50		Loss of ubiquitination at K404 (P = 0.0768);.;
MVP		0.93
MPC		0.18
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.51
gMVP		0.77

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: rs137852924; hg19: chr4-5642516;