rs12572862

chr10-27033374-C-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.3658G>C(p.Val1220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,608,624 control chromosomes in the GnomAD database, including 1,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (156 hom., cov: 32)
  • Exomes 𝑓: 0.017 (1645 hom.)
• Consequence: ANKRD26 NM_014915.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.416

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=0.0017209053).
• BP6: Variant 10-27033374-C-G is Benign according to our data. Variant chr10-27033374-C-G is described in ClinVar as [Benign]. Clinvar id is 260466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-27033374-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD26	NM_014915.3	c.3658G>C	p.Val1220Leu	missense_variant	25/34	ENST00000376087.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD26	ENST00000376087.5	c.3658G>C	p.Val1220Leu	missense_variant	25/34	5	NM_014915.3	A2
ANKRD26	ENST00000436985.7	c.3655G>C	p.Val1219Leu	missense_variant	25/34	1		P4
ANKRD26	ENST00000675936.1	c.76G>C	p.Val26Leu	missense_variant, NMD_transcript_variant	2/13
ANKRD26	ENST00000675116.1	c.1309G>C	p.Val437Leu	missense_variant, NMD_transcript_variant	5/15

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2509 AN: 152080 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0547

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.0357 AC: 8895 AN: 249158 Hom.: 465 AF XY: 0.0388 AC XY: 5250 AN XY: 135166

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0569

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0169 AC: 24559 AN: 1456426 Hom.: 1645 Cov.: 31 AF XY: 0.0196 AC XY: 14192 AN XY: 724464

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.0530

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0165 AC: 2505 AN: 152198 Hom.: 156 Cov.: 32 AF XY: 0.0220 AC XY: 1636 AN XY: 74412

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.0547

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00594 Hom.: 7

Bravo AF: 0.0112

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000272 AC: 1

ESP6500EA AF: 0.00220 AC: 18

ExAC AF: 0.0359 AC: 4339

Asia WGS AF: 0.117 AC: 406 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 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	0.32
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.9
Dann	Benign	0.90
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.074	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.096
Sift	Benign	0.070	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.033
MPC		0.055
ClinPred		0.0066	T
GERP RS		-3.7
Varity_R		0.054
gMVP		0.031

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: rs12572862; hg19: chr10-27322303; COSMIC: COSV65774350; COSMIC: COSV65774350;