rs149655759

Positions:

• chr10-27060339-A-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.1564+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,595,366 control chromosomes in the GnomAD database, including 428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 32)
  • Exomes 𝑓: 0.022 (396 hom.)
• Consequence: ANKRD26 NM_014915.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.03147
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.601

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 (BayesDel_noAF=-0.67).
• BP6: Variant 10-27060339-A-G is Benign according to our data. Variant chr10-27060339-A-G is described in ClinVar as [Benign]. Clinvar id is 260459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-27060339-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2573/152266) while in subpopulation NFE AF= 0.0256 (1739/68020). AF 95% confidence interval is 0.0246. There are 32 homozygotes in gnomad4. There are 1210 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2573 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD26	NM_014915.3	c.1564+6T>C		splice_donor_region_variant, intron_variant		ENST00000376087.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD26	ENST00000376087.5	c.1564+6T>C		splice_donor_region_variant, intron_variant		5	NM_014915.3	A2

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2573 AN: 152148 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0186 AC: 4636 AN: 249110 Hom.: 70 AF XY: 0.0187 AC XY: 2532 AN XY: 135132

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.00615

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.00261

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0220 AC: 31725 AN: 1443100 Hom.: 396 Cov.: 30 AF XY: 0.0219 AC XY: 15746 AN XY: 719056

Gnomad4 AFR exome AF: 0.00285

Gnomad4 AMR exome AF: 0.00703

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.00119

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.0282

Gnomad4 NFE exome AF: 0.0242

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0169 AC: 2573 AN: 152266 Hom.: 32 Cov.: 32 AF XY: 0.0163 AC XY: 1210 AN XY: 74444

Gnomad4 AFR AF: 0.00397

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0228 Hom.: 15

Bravo AF: 0.0147

Asia WGS AF: 0.0160 AC: 56 AN: 3474

EpiCase AF: 0.0248

EpiControl AF: 0.0218

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Thrombocytopenia 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
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 12, 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:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.5
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.031
dbscSNV1_RF	Benign	0.23
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: rs149655759; hg19: chr10-27349268;