rs12572862

Variant names:

• chr10-27033374-C-G
• rs12572862
• NM_014915.3:c.3658G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:8
• Conservation: PhyloP100: 0.416
• Publications: 9 publications found

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]

ANKRD26 Gene-Disease associations (from GenCC):

• thrombocytopenia 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal thrombocytopenia with normal platelets

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 260466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014915.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	NM_014915.3	MANE Select	c.3658G>C	p.Val1220Leu	missense	Exon 25 of 34	NP_055730.2	Q9UPS8-1
	ANKRD26	NM_001256053.2		c.3655G>C	p.Val1219Leu	missense	Exon 25 of 34	NP_001242982.1	E7ESJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD26	ENST00000376087.5	TSL:5 MANE Select	c.3658G>C	p.Val1220Leu	missense	Exon 25 of 34	ENSP00000365255.4	Q9UPS8-1
	ANKRD26	ENST00000436985.7	TSL:1	c.3655G>C	p.Val1219Leu	missense	Exon 25 of 34	ENSP00000405112.3	E7ESJ3
	ANKRD26	ENST00000968143.1		c.4744G>C	p.Val1582Leu	missense	Exon 26 of 35	ENSP00000638202.1

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

GnomAD2 exomes AF: 0.0357 AC: 8895 AN: 249158 AF XY: 0.0388

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 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

African (AFR) AF: 0.000718 AC: 24 AN: 33434

American (AMR) AF: 0.0274 AC: 1223 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 261 AN: 26014

East Asian (EAS) AF: 0.203 AC: 8032 AN: 39470

South Asian (SAS) AF: 0.111 AC: 9483 AN: 85188

European-Finnish (FIN) AF: 0.0530 AC: 2813 AN: 53066

Middle Eastern (MID) AF: 0.00873 AC: 50 AN: 5728

European-Non Finnish (NFE) AF: 0.00140 AC: 1554 AN: 1108786

Other (OTH) AF: 0.0186 AC: 1119 AN: 60066

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

African (AFR) AF: 0.00108 AC: 45 AN: 41552

American (AMR) AF: 0.0143 AC: 219 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.158 AC: 816 AN: 5176

South Asian (SAS) AF: 0.128 AC: 616 AN: 4826

European-Finnish (FIN) AF: 0.0547 AC: 578 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 67992

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Thrombocytopenia 2 (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.074	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.42
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.096
Sift	Benign	0.070	T
Sift4G	Benign	0.27	T
Vest4		0.033
MPC		0.055
ClinPred		0.0066	T
GERP RS		-3.7
Varity_R		0.054
gMVP		0.031
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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