Genetic Variant NM_021220.4:c.327C>A (chr20-18041718-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_021220.4(OVOL2):c.327C>A(p.Thr109Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 1,610,476 control chromosomes in the GnomAD database, including 3,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.057 ( 286 hom., cov: 31)

Exomes 𝑓: 0.065 ( 3530 hom. )

Consequence

OVOL2
NM_021220.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.157

Publications

9 publications found

Variant links:

Genes affected

OVOL2 (HGNC:15804): (ovo like zinc finger 2) This gene encodes a member of the evolutionarily conserved ovo-like protein family. Mammalian members of this family contain a single zinc finger domain composed of a tetrad of C2H2 zinc fingers with variable N- and C-terminal extensions that contain intrinsically disordered domains. Members of this family are involved in epithelial development and differentiation. Knockout of this gene in mouse results in early embryonic lethality with phenotypes that include neurectoderm expansion, impaired vascularization, and heart anomalies. In humans, allelic variants of this gene have been associated with posterior polymorphous corneal dystrophy. [provided by RefSeq, Apr 2016]

OVOL2 Gene-Disease associations (from GenCC):

posterior polymorphous corneal dystrophy 1
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
congenital hereditary endothelial dystrophy type I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
posterior polymorphous corneal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

OVOL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 20-18041718-G-T is Benign according to our data. Variant chr20-18041718-G-T is described in ClinVar as Benign. ClinVar VariationId is 2037537.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.157 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
OVOL2	NM_021220.4 link	c.327C>A	p.Thr109Thr	synonymous_variant	Exon 3 of 4	ENST00000278780.7	NP_067043.2
OVOL2	NM_001303461.1 link	c.-70C>A		5_prime_UTR_variant	Exon 3 of 4		NP_001290390.1
OVOL2	NM_001303462.1 link	c.-70C>A		5_prime_UTR_variant	Exon 2 of 3		NP_001290391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OVOL2	ENST00000278780.7 link	c.327C>A	p.Thr109Thr	synonymous_variant	Exon 3 of 4	1	NM_021220.4	ENSP00000278780.5		Q9BRP0-1

Frequencies

GnomAD3 genomes

AF:

0.0570

AC:

8654

AN:

151878

Hom.:

286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0730

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0289

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.0353

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0671

Gnomad OTH

AF:

0.0465

GnomAD2 exomes

AF:

0.0435

AC:

10855

AN:

249776

AF XY:

0.0439

show subpopulations

Gnomad AFR exome

AF:

0.0707

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.00294

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0622

Gnomad OTH exome

AF:

0.0393

GnomAD4 exome

AF:

0.0647

AC:

94396

AN:

1458480

Hom.:

3530

Cov.:

AF XY:

0.0633

AC XY:

45879

AN XY:

725028

show subpopulations

African (AFR)

AF:

0.0699

AC:

2336

AN:

33408

American (AMR)

AF:

0.0212

AC:

945

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

685

AN:

26100

East Asian (EAS)

AF:

0.00187

AC:

AN:

39602

South Asian (SAS)

AF:

0.0336

AC:

2892

AN:

86172

European-Finnish (FIN)

AF:

0.0254

AC:

1352

AN:

53332

Middle Eastern (MID)

AF:

0.0247

AC:

129

AN:

5232

European-Non Finnish (NFE)

AF:

0.0741

AC:

82232

AN:

1109784

Other (OTH)

AF:

0.0623

AC:

3751

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

4439

8879

13318

17758

22197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3116

6232

9348

12464

15580

<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:

0.0570

AC:

8664

AN:

151996

Hom.:

286

Cov.:

AF XY:

0.0537

AC XY:

3993

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0730

AC:

3024

AN:

41416

American (AMR)

AF:

0.0288

AC:

440

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3470

East Asian (EAS)

AF:

0.00483

AC:

AN:

5172

South Asian (SAS)

AF:

0.0355

AC:

170

AN:

4782

European-Finnish (FIN)

AF:

0.0240

AC:

255

AN:

10606

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0671

AC:

4563

AN:

67982

Other (OTH)

AF:

0.0460

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

403

806

1208

1611

2014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0607

Hom.:

585

Bravo

AF:

0.0581

Asia WGS

AF:

0.0290

AC:

101

AN:

3478

EpiCase

AF:

0.0629

EpiControl

AF:

0.0580

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.6

(source)

DANN

Benign

0.62

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism (auto)

(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

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