rs139949439

Positions:

• chr10-27040008-C-G

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.2332G>C​(p.Glu778Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00321 in 1,613,662 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (9 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.96

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=0.009538174).
• BP6: Variant 10-27040008-C-G is Benign according to our data. Variant chr10-27040008-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 434202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (365/152322) while in subpopulation NFE AF= 0.00397 (270/68022). AF 95% confidence interval is 0.00358. There are 2 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 365 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD26	NM_014915.3	c.2332G>C	p.Glu778Gln	missense_variant	21/34	ENST00000376087.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD26	ENST00000376087.5	c.2332G>C	p.Glu778Gln	missense_variant	21/34	5	NM_014915.3	A2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00221 AC: 552 AN: 249402 Hom.: 1 AF XY: 0.00225 AC XY: 304 AN XY: 135330

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00329 AC: 4810 AN: 1461340 Hom.: 9 Cov.: 31 AF XY: 0.00325 AC XY: 2365 AN XY: 727010

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00388

Gnomad4 NFE exome AF: 0.00387

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74484

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00363 Hom.: 2

Bravo AF: 0.00200

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000817 AC: 3

ESP6500EA AF: 0.00417 AC: 34

ExAC AF: 0.00243 AC: 293

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ANKRD26: BP4, BS1, BS2 -

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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	0.74	D;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.016	D;D
Vest4		0.22
MVP		0.19
MPC		0.32
ClinPred		0.012	T
GERP RS		3.3
Varity_R		0.24
gMVP		0.022

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: rs139949439; hg19: chr10-27328937;