rs61745662

chr10-27035472-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014915.3(ANKRD26):c.2978A>C(p.Glu993Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00417 in 1,614,024 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (130 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.45

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=0.002908945).
• BP6: Variant 10-27035472-T-G is Benign according to our data. Variant chr10-27035472-T-G is described in ClinVar as [Benign]. Clinvar id is 260464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD26	NM_014915.3	c.2978A>C	p.Glu993Ala	missense_variant	24/34	ENST00000376087.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD26	ENST00000376087.5	c.2978A>C	p.Glu993Ala	missense_variant	24/34	5	NM_014915.3	A2
ANKRD26	ENST00000436985.7	c.2975A>C	p.Glu992Ala	missense_variant	24/34	1		P4
ANKRD26	ENST00000675349.1	n.2707A>C		non_coding_transcript_exon_variant	9/9
ANKRD26	ENST00000675116.1	c.629A>C	p.Glu210Ala	missense_variant, NMD_transcript_variant	4/15

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3346 AN: 152130 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0769

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00555 AC: 1385 AN: 249442 Hom.: 46 AF XY: 0.00427 AC XY: 578 AN XY: 135340

Gnomad AFR exome AF: 0.0806

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00231 AC: 3382 AN: 1461776 Hom.: 130 Cov.: 32 AF XY: 0.00198 AC XY: 1437 AN XY: 727186

Gnomad4 AFR exome AF: 0.0838

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.00513

GnomAD4 genome AF: 0.0220 AC: 3348 AN: 152248 Hom.: 133 Cov.: 32 AF XY: 0.0212 AC XY: 1579 AN XY: 74448

Gnomad4 AFR AF: 0.0767

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00383 Hom.: 40

Bravo AF: 0.0254

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0741 AC: 279

ESP6500EA AF: 0.000607 AC: 5

ExAC AF: 0.00645 AC: 779

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia 2 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Benign	0.18
Sift	Benign	0.051	T;T
Sift4G	Uncertain	0.017	D;D
Vest4		0.33
MVP		0.41
MPC		0.23
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.31
gMVP		0.088

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: rs61745662; hg19: chr10-27324401;