4-5628743-TAA-TAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_147127.5(EVC2):c.1711-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 32 hom., cov: 0)

Exomes 𝑓: 0.013 ( 12 hom. )

Consequence

EVC2
NM_147127.5 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.151

Publications

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

EVC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 4-5628743-T-TA is Benign according to our data. Variant chr4-5628743-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1168233.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 = 0.0123 (1828/148734) while in subpopulation AFR AF = 0.0399 (1634/40936). AF 95% confidence interval is 0.0383. There are 32 homozygotes in GnomAd4. There are 872 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.1711-10dupT		intron_variant	Intron 11 of 21	ENST00000344408.10	NP_667338.3	Q86UK5-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC2	ENST00000344408.10 link	c.1711-10dupT	intron_variant	Intron 11 of 21	1	NM_147127.5	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6 link	c.1471-10dupT	intron_variant	Intron 11 of 21	1		ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5 link	n.1471-10dupT	intron_variant	Intron 11 of 22	1		ENSP00000431981.1	A0A0C4DGE7
EVC2	ENST00000509670.1 link	n.*104-10dupT	intron_variant	Intron 12 of 22	1		ENSP00000423876.1	E9PFT2

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1827

AN:

148626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0400

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00581

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0109

Gnomad FIN

AF:

0.000618

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000330

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0108

AC:

2028

AN:

187796

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.0492

Gnomad AMR exome

AF:

0.00691

Gnomad ASJ exome

AF:

0.00553

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.00796

Gnomad NFE exome

AF:

0.00455

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.0126

AC:

14991

AN:

1193360

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

7324

AN XY:

592584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0540

AC:

1676

AN:

31030

American (AMR)

AF:

0.00758

AC:

290

AN:

38272

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

211

AN:

20526

East Asian (EAS)

AF:

0.00225

AC:

AN:

35086

South Asian (SAS)

AF:

0.0216

AC:

1481

AN:

68674

European-Finnish (FIN)

AF:

0.00943

AC:

412

AN:

43706

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

4802

European-Non Finnish (NFE)

AF:

0.0112

AC:

10104

AN:

901848

Other (OTH)

AF:

0.0136

AC:

674

AN:

49416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

1936

3872

5807

7743

9679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.0123

AC:

1828

AN:

148734

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

872

AN XY:

72486

show subpopulations

African (AFR)

AF:

0.0399

AC:

1634

AN:

40936

American (AMR)

AF:

0.00581

AC:

AN:

14986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

5096

South Asian (SAS)

AF:

0.0107

AC:

AN:

4654

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

9716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000330

AC:

AN:

66702

Other (OTH)

AF:

0.0141

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0272

Hom.:

399

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:2

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 20, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over