rs2304877

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000037.4(ANK1):c.1856G>A(p.Arg619His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,614,060 control chromosomes in the GnomAD database, including 2,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 202 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2022 hom. )

Consequence

ANK1
NM_000037.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.64

Publications

24 publications found

Variant links:

Genes affected

ANK1 (HGNC:492): (ankyrin 1) Ankyrins are a family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 1, the prototype of this family, was first discovered in the erythrocytes, but since has also been found in brain and muscles. Mutations in erythrocytic ankyrin 1 have been associated in approximately half of all patients with hereditary spherocytosis. Complex patterns of alternative splicing in the regulatory domain, giving rise to different isoforms of ankyrin 1 have been described. Truncated muscle-specific isoforms of ankyrin 1 resulting from usage of an alternate promoter have also been identified. [provided by RefSeq, Dec 2008]

ANK1 Gene-Disease associations (from GenCC):

hereditary spherocytosis
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
hereditary spherocytosis type 1
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ANK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045528114).

BP6

Variant 8-41708920-C-T is Benign according to our data. Variant chr8-41708920-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.1856G>A	p.Arg619His	missense_variant	Exon 17 of 43	ENST00000289734.13	NP_000028.3	P16157-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13 link	c.1856G>A	p.Arg619His	missense_variant	Exon 17 of 43	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7166

AN:

152122

Hom.:

200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0546

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0410

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.0367

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.0408

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.0444

AC:

11169

AN:

251420

AF XY:

0.0409

show subpopulations

Gnomad AFR exome

AF:

0.0534

Gnomad AMR exome

AF:

0.0693

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.0374

Gnomad FIN exome

AF:

0.0414

Gnomad NFE exome

AF:

0.0474

Gnomad OTH exome

AF:

0.0394

GnomAD4 exome

AF:

0.0501

AC:

73275

AN:

1461820

Hom.:

2022

Cov.:

AF XY:

0.0483

AC XY:

35118

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0596

AC:

1997

AN:

33480

American (AMR)

AF:

0.0669

AC:

2991

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

685

AN:

26136

East Asian (EAS)

AF:

0.0473

AC:

1877

AN:

39700

South Asian (SAS)

AF:

0.0151

AC:

1300

AN:

86258

European-Finnish (FIN)

AF:

0.0395

AC:

2110

AN:

53354

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0536

AC:

59617

AN:

1112008

Other (OTH)

AF:

0.0433

AC:

2615

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4551

9102

13653

18204

22755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2346

4692

7038

9384

11730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0472

AC:

7183

AN:

152240

Hom.:

202

Cov.:

AF XY:

0.0454

AC XY:

3379

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0547

AC:

2271

AN:

41536

American (AMR)

AF:

0.0410

AC:

627

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3472

East Asian (EAS)

AF:

0.0369

AC:

191

AN:

5170

South Asian (SAS)

AF:

0.0112

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0408

AC:

433

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0495

AC:

3367

AN:

68002

Other (OTH)

AF:

0.0398

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

349

698

1046

1395

1744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0475

Hom.:

283

Bravo

AF:

0.0484

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0532

AC:

205

ESP6500AA

AF:

0.0547

AC:

241

ESP6500EA

AF:

0.0488

AC:

420

ExAC

AF:

0.0435

AC:

5283

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.0417

EpiControl

AF:

0.0469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10745622) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spherocytosis

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;L;.

PhyloP100

2.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.099

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.020

B;B;B

Vest4

0.13

MPC

0.37

ClinPred

0.0078

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.27

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over