rs1442611750

Variant names:

• chr10-27017672-T-C
• rs1442611750
• NM_014915.3:c.4336A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_014915.3(ANKRD26):​c.4336A>G​(p.Lys1446Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1446Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.853
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13490742).
• BP6: Variant 10-27017672-T-C is Benign according to our data. Variant chr10-27017672-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434207.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014915.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	NM_014915.3	MANE Select	c.4336A>G	p.Lys1446Glu	missense	Exon 30 of 34	NP_055730.2
	ANKRD26	NM_001256053.2		c.4333A>G	p.Lys1445Glu	missense	Exon 30 of 34	NP_001242982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	ENST00000376087.5	TSL:5 MANE Select	c.4336A>G	p.Lys1446Glu	missense	Exon 30 of 34	ENSP00000365255.4
	ANKRD26	ENST00000436985.7	TSL:1	c.4333A>G	p.Lys1445Glu	missense	Exon 30 of 34	ENSP00000405112.3
	ANKRD26	ENST00000676280.1		c.163A>G	p.Lys55Glu	missense	Exon 2 of 4	ENSP00000502438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248842 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461222 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726922

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1446E variant (also known as c.4336A>G), located in coding exon 30 of the ANKRD26 gene, results from an A to G substitution at nucleotide position 4336. The lysine at codon 1446 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

not specified Benign:1

Jun 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.97
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.076	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.85
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.047
Sift	Benign	0.043	D
Sift4G	Benign	0.12	T
Vest4		0.27
MVP		0.21
MPC		0.26
ClinPred		0.14	T
GERP RS		3.6
Varity_R		0.20
gMVP		0.033
Mutation Taster		=97/3	polymorphism

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: rs1442611750; hg19: chr10-27306601;