rs6820907

Variant names:

• chr4-5708462-G-A
• rs6820907
• NM_147127.5:c.52C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147127.5(EVC2):​c.52C>T​(p.Leu18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,505,760 control chromosomes in the GnomAD database, including 15,591 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (2994 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12597 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0250
• Publications: 10 publications found

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]

EVC2 Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004922539).
• BP6: Variant 4-5708462-G-A is Benign according to our data. Variant chr4-5708462-G-A is described in ClinVar as Benign. ClinVar VariationId is 262618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 1 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.-13+367C>T		intron	N/A	NP_001159608.1	Q86UK5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 1 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.-13+367C>T		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.-13+367C>T		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.178 AC: 26979 AN: 151866 Hom.: 2982 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.152 AC: 15220 AN: 100284 AF XY: 0.149

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.0984

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.128 AC: 173268 AN: 1353784 Hom.: 12597 Cov.: 31 AF XY: 0.129 AC XY: 85908 AN XY: 667562

African (AFR) AF: 0.311 AC: 8587 AN: 27608

American (AMR) AF: 0.208 AC: 6864 AN: 33062

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2487 AN: 24084

East Asian (EAS) AF: 0.244 AC: 7790 AN: 31934

South Asian (SAS) AF: 0.187 AC: 14228 AN: 76252

European-Finnish (FIN) AF: 0.122 AC: 4065 AN: 33296

Middle Eastern (MID) AF: 0.113 AC: 455 AN: 4014

European-Non Finnish (NFE) AF: 0.114 AC: 121234 AN: 1067036

Other (OTH) AF: 0.134 AC: 7558 AN: 56498

GnomAD4 genome AF: 0.178 AC: 27045 AN: 151976 Hom.: 2994 Cov.: 32 AF XY: 0.179 AC XY: 13287 AN XY: 74282

African (AFR) AF: 0.302 AC: 12526 AN: 41490

American (AMR) AF: 0.189 AC: 2894 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 359 AN: 3460

East Asian (EAS) AF: 0.177 AC: 900 AN: 5086

South Asian (SAS) AF: 0.192 AC: 925 AN: 4824

European-Finnish (FIN) AF: 0.113 AC: 1193 AN: 10600

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.112 AC: 7598 AN: 67926

Other (OTH) AF: 0.165 AC: 349 AN: 2112

Alfa AF: 0.0792 Hom.: 153

Bravo AF: 0.187

TwinsUK AF: 0.115 AC: 428

ALSPAC AF: 0.118 AC: 455

ExAC AF: 0.0976 AC: 2186

Asia WGS AF: 0.237 AC: 824 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ellis-van Creveld syndrome (2)
-	-	2	not provided (2)
-	-	1	Curry-Hall syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.025
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.24
Sift	Benign	0.075	T
Sift4G	Uncertain	0.036	D
Polyphen		0.72	P
Vest4		0.029
MPC		0.021
ClinPred		0.0030	T
GERP RS		-1.8
PromoterAI		-0.091	Neutral
Varity_R		0.063
gMVP		0.12
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6820907; hg19: chr4-5710189; COSMIC: COSV53828801; COSMIC: COSV53828801;