EVC2 p.Ala305Ser

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_147127.5(EVC2):c.913G>T(p.Ala305Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,614,192 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 6 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.48

Publications

2 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women's Health, Laboratory for Molecular Medicine

EVC2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_147127.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042190433).

BP6

Variant 4-5665607-C-A is Benign according to our data. Variant chr4-5665607-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461812.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000821 (125/152312) while in subpopulation AMR AF = 0.00444 (68/15306). AF 95% confidence interval is 0.0036. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD gene

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.913G>T	p.Ala305Ser	missense	Exon 8 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.673G>T	p.Ala225Ser	missense	Exon 8 of 22	NP_001159608.1	Q86UK5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EVC2	ENST00000344408.10	TSL:1 MANE Select	c.913G>T	p.Ala305Ser	missense	Exon 8 of 22	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6	TSL:1	c.673G>T	p.Ala225Ser	missense	Exon 8 of 22	ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5	TSL:1	n.673G>T		non_coding_transcript_exon	Exon 8 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000537

AC:

135

AN:

251440

AF XY:

0.000596

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000624

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.000411

AC:

601

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

323

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000939

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00110

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000334

AC:

371

AN:

1112010

Other (OTH)

AF:

0.000695

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000821

AC:

125

AN:

152312

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41586

American (AMR)

AF:

0.00444

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000580

Hom.:

Bravo

AF:

0.00144

EpiCase

AF:

0.00142

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Ellis-van Creveld syndrome (1)

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

EVC2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.69

M_CAP

Benign

0.051

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.4

PhyloP100

1.5

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.34

Sift

Benign

0.044

Sift4G

Pathogenic

0.0

Varity_R

0.11

gMVP

0.37

Mutation Taster

=95/5

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over