rs199849785

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_014915.3(ANKRD26):c.92G>C(p.Gly31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,612,304 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

ANKRD26
NM_014915.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.814

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039687157).

BP6

Variant 10-27100235-C-G is Benign according to our data. Variant chr10-27100235-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434205.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00186 (284/152364) while in subpopulation AFR AF = 0.0064 (266/41592). AF 95% confidence interval is 0.00576. There are 1 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 284 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD26	NM_014915.3 link	c.92G>C	p.Gly31Ala	missense_variant	Exon 1 of 34	ENST00000376087.5	NP_055730.2	Q9UPS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD26	ENST00000376087.5 link	c.92G>C	p.Gly31Ala	missense_variant	Exon 1 of 34	5	NM_014915.3	ENSP00000365255.4		Q9UPS8-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00641

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000602

AC:

148

AN:

246022

AF XY:

0.000477

show subpopulations

Gnomad AFR exome

AF:

0.00812

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000239

AC:

349

AN:

1459940

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

726358

show subpopulations

African (AFR)

AF:

0.00819

AC:

274

AN:

33468

American (AMR)

AF:

0.000336

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51922

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111738

Other (OTH)

AF:

0.000530

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00186

AC:

284

AN:

152364

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00640

AC:

266

AN:

41592

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000218

Hom.:

Bravo

AF:

0.00230

ESP6500AA

AF:

0.00291

AC:

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.000638

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

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.Gly31Ala variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs199849785) and ClinVar (classified as likely benign by Genetic Services Laboratory, University of Chicago). The variant was identified in control databases in 211 of 277410 chromosomes (1 homozygous) at a frequency of 0.000761 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 185 of 23856 chromosomes (freq: 0.007755), Other in 3 of 7092 chromosomes (freq: 0.000423), Latino in 9 of 35314 chromosomes (freq: 0.000255), East Asian in 2 of 19418 chromosomes (freq: 0.000103) and European (non-Finnish) in 12 of 126830 chromosomes (freq: 0.000095), but not in the Ashkenazi Jewish, European (Finnish), and South Asian populations. The p.Gly31 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANKRD26: BP4, BS1 -

Thrombocytopenia 2

Benign:2

Jan 12, 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. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.92G>C (p.G31A) alteration is located in exon 1 (coding exon 1) of the ANKRD26 gene. This alteration results from a G to C substitution at nucleotide position 92, causing the glycine (G) at amino acid position 31 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Jul 26, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

Benign

0.092

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.1

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.035

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.26

.;N

PhyloP100

-0.81

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.012

Sift

Benign

0.73

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.0040

.;B

Vest4

0.080

MVP

0.11

MPC

0.051

ClinPred

0.0044

GERP RS

-0.45

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.30

Mutation Taster

=100/0

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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