rs191015656

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP3BP4_ModerateBP6_Very_StrongBS1BS2

The NM_014915.3(ANKRD26):c.542C>T(p.Thr181Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,613,062 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T181P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

ANKRD26
NM_014915.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 7.54

Publications

9 publications found

Variant links:

Genes affected

ANKRD26 (HGNC:29186): (ankyrin repeat domain containing 26) This gene encodes a protein containing N-terminal ankyrin repeats which function in protein-protein interactions. Mutations in this gene are associated with autosomal dominant thrombocytopenia-2. Pseudogenes of this gene are found on chromosome 7, 10, 13 and 16. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ANKRD26 Gene-Disease associations (from GenCC):

thrombocytopenia 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
autosomal thrombocytopenia with normal platelets
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ANKRD26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.12240374).

BP6

Variant 10-27092502-G-A is Benign according to our data. Variant chr10-27092502-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000893 (136/152268) while in subpopulation AMR AF = 0.0015 (23/15294). AF 95% confidence interval is 0.00116. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD26	NM_014915.3 link	c.542C>T	p.Thr181Ile	missense_variant	Exon 4 of 34	ENST00000376087.5	NP_055730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD26	ENST00000376087.5 link	c.542C>T	p.Thr181Ile	missense_variant	Exon 4 of 34	5	NM_014915.3	ENSP00000365255.4

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00111

AC:

277

AN:

248874

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000754

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.00140

AC:

2050

AN:

1460794

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

974

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33470

American (AMR)

AF:

0.00224

AC:

100

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.000831

AC:

AN:

52964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00164

AC:

1824

AN:

1111496

Other (OTH)

AF:

0.00114

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

183

274

366

457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.000893

AC:

136

AN:

152268

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41560

American (AMR)

AF:

0.00150

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

68024

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00139

Hom.:

Bravo

AF:

0.00104

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00147

AC:

ExAC

AF:

0.00121

AC:

146

EpiCase

AF:

0.00180

EpiControl

AF:

0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in association with increased platelet aggregation (Chen 2017); This variant is associated with the following publications: (PMID: 27535533, 29185836)

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ANKRD26 p.T181I variant was not identified in the literature but was identified in dbSNP (ID: rs191015656) and ClinVar (classified as likely benign by University of Chicago; and as benign by Invitae and Illumina). The variant was identified in control databases in 307 of 280276 chromosomes (0 homozygous) at a frequency of 0.001095, and was observed at the highest frequency in the European (non-Finnish) population in 186 of 128500 chromosomes (freq: 0.001447) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T181 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANKRD26: BS1, BS2

Thrombocytopenia 2

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jun 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jun 20, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANKRD26-related disorder

Benign:1

May 12, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.12

T;T

MetaSVM

Pathogenic

0.79

MutationAssessor

Benign

0.0

.;M

PhyloP100

7.5

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.78

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.0070

D;D

Vest4

0.83

ClinPred

0.065

GERP RS

4.3

Varity_R

0.34

gMVP

0.66

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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