NM_014915.3:c.2332G>C

Variant names:

• chr10-27040008-C-G
• rs139949439
• NM_014915.3:c.2332G>C

Variant summary

Our verdict is Benign. The variant received -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:10
• Conservation: PhyloP100: 3.96
• Publications: 10 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=0.009538174).
• BP6: Variant 10-27040008-C-G is Benign according to our data. Variant chr10-27040008-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 365 AD gene.

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.2332G>C	p.Glu778Gln	missense	Exon 21 of 34	NP_055730.2	Q9UPS8-1
	ANKRD26	NM_001256053.2		c.2329G>C	p.Glu777Gln	missense	Exon 21 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.2332G>C	p.Glu778Gln	missense	Exon 21 of 34	ENSP00000365255.4	Q9UPS8-1
	ANKRD26	ENST00000436985.7	TSL:1	c.2329G>C	p.Glu777Gln	missense	Exon 21 of 34	ENSP00000405112.3	E7ESJ3
	ANKRD26	ENST00000968143.1		c.3418G>C	p.Glu1140Gln	missense	Exon 22 of 35	ENSP00000638202.1

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

GnomAD2 exomes AF: 0.00221 AC: 552 AN: 249402 AF XY: 0.00225

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33460

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86234

European-Finnish (FIN) AF: 0.00388 AC: 207 AN: 53374

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5706

European-Non Finnish (NFE) AF: 0.00387 AC: 4301 AN: 1111766

Other (OTH) AF: 0.00247 AC: 149 AN: 60364

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

African (AFR) AF: 0.000698 AC: 29 AN: 41562

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00397 AC: 270 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Thrombocytopenia 2 (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.82	T
PhyloP100		4.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.14
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.016	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
Mutation Taster		=99/1	polymorphism

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: rs139949439; hg19: chr10-27328937;