rs146159734

chr10-27017749-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014915.3(ANKRD26):c.4259G>A(p.Cys1420Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,613,164 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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. C1420F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (26 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.113

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01960659).
• BP6: Variant 10-27017749-C-T is Benign according to our data. Variant chr10-27017749-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00169 (258/152292) while in subpopulation SAS AF= 0.0102 (49/4824). AF 95% confidence interval is 0.00789. There are 0 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 259 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD26	NM_014915.3	c.4259G>A	p.Cys1420Tyr	missense_variant	30/34	ENST00000376087.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD26	ENST00000376087.5	c.4259G>A	p.Cys1420Tyr	missense_variant	30/34	5	NM_014915.3	A2

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00333 AC: 826 AN: 248244 Hom.: 11 AF XY: 0.00383 AC XY: 516 AN XY: 134676

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.00192

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00614

GnomAD4 exome AF: 0.00235 AC: 3438 AN: 1460872 Hom.: 26 Cov.: 31 AF XY: 0.00266 AC XY: 1930 AN XY: 726742

Gnomad4 AFR exome AF: 0.000748

Gnomad4 AMR exome AF: 0.00336

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00145

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74468

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00189

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00209 AC: 17

ExAC AF: 0.00350 AC: 423

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.00305

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	This variant is associated with the following publications: (PMID: 29185836, 27931139, 28748566) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 15, 2016

- -

ANKRD26-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

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	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	17
Dann	Benign	0.68
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	0.50	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Uncertain	0.45
Sift	Benign	0.095	T;T
Sift4G	Benign	0.24	T;T
Vest4		0.31
MVP		0.52
MPC		0.088
ClinPred		0.022	T
GERP RS		0.71
Varity_R		0.29
gMVP		0.044

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

LitVar

Other links and lift over

dbSNP: rs146159734; hg19: chr10-27306678; COSMIC: COSV105828142; COSMIC: COSV105828142;