10-27100268-T-C

Variant names:

• chr10-27100268-T-C
• rs7897309
• NM_014915.3:c.59A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014915.3(ANKRD26):​c.59A>G​(p.Gln20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,610,676 control chromosomes in the GnomAD database, including 612,103 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q20Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.90 (62363 hom., cov: 34)
  • Exomes 𝑓: 0.87 (549740 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.09
• Publications: 28 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.475063E-7).
• BP6: Variant 10-27100268-T-C is Benign according to our data. Variant chr10-27100268-T-C is described in ClinVar as Benign. ClinVar VariationId is 260472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD26	NM_014915.3	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 34	ENST00000376087.5	NP_055730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD26	ENST00000376087.5	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 34	5	NM_014915.3	ENSP00000365255.4

Frequencies

GnomAD3 genomes AF: 0.903 AC: 137435 AN: 152202 Hom.: 62298 Cov.: 34

Gnomad AFR AF: 0.972

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.902

Gnomad ASJ AF: 0.872

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.931

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.887

GnomAD2 exomes AF: 0.899 AC: 218953 AN: 243526 AF XY: 0.896

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.933

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.853

Gnomad OTH exome AF: 0.882

GnomAD4 exome AF: 0.867 AC: 1264775 AN: 1458356 Hom.: 549740 Cov.: 86 AF XY: 0.868 AC XY: 629994 AN XY: 725536

African (AFR) AF: 0.975 AC: 32610 AN: 33444

American (AMR) AF: 0.929 AC: 41492 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 22834 AN: 26088

East Asian (EAS) AF: 1.00 AC: 39657 AN: 39668

South Asian (SAS) AF: 0.918 AC: 79135 AN: 86206

European-Finnish (FIN) AF: 0.925 AC: 47114 AN: 50946

Middle Eastern (MID) AF: 0.866 AC: 4848 AN: 5600

European-Non Finnish (NFE) AF: 0.849 AC: 944099 AN: 1111452

Other (OTH) AF: 0.879 AC: 52986 AN: 60294

GnomAD4 genome AF: 0.903 AC: 137559 AN: 152320 Hom.: 62363 Cov.: 34 AF XY: 0.909 AC XY: 67724 AN XY: 74486

African (AFR) AF: 0.972 AC: 40443 AN: 41594

American (AMR) AF: 0.902 AC: 13798 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 3026 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5179 AN: 5182

South Asian (SAS) AF: 0.923 AC: 4454 AN: 4828

European-Finnish (FIN) AF: 0.931 AC: 9882 AN: 10612

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57899 AN: 68014

Other (OTH) AF: 0.888 AC: 1877 AN: 2114

Alfa AF: 0.862 Hom.: 48055

Bravo AF: 0.904

TwinsUK AF: 0.849 AC: 3149

ALSPAC AF: 0.855 AC: 3297

ESP6500AA AF: 0.973 AC: 3584

ESP6500EA AF: 0.857 AC: 6982

ExAC AF: 0.896 AC: 107448

Asia WGS AF: 0.967 AC: 3362 AN: 3478

EpiCase AF: 0.855

EpiControl AF: 0.855

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia 2 Benign:3

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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

- -

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. -

not provided Benign:3

Nov 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21467542) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 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
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.076
DANN	Benign	0.66
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	8.5e-7	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	.;N
PhyloP100		-1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.0050
Sift	Benign	1.0	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.0	.;B
Vest4		0.043
MPC		0.049
ClinPred		0.0022	T
GERP RS		-1.1
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7897309; hg19: chr10-27389197; COSMIC: COSV65793917;