rs2304877

Positions:

chr8-41708920-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 14/20 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:7

Conservation

PhyloP100: 2.64

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK1. . Gene score misZ 2.0781 (greater than the threshold 3.09). Trascript score misZ 3.8314 (greater than threshold 3.09). GenCC has associacion of gene with hereditary spherocytosis type 1, hereditary spherocytosis.

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. Variant chr8-41708920-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
ANK1	NM_000037.4 linkuse as main transcript	c.1856G>A	p.Arg619His	missense_variant	17/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13 linkuse as main transcript	c.1856G>A	p.Arg619His	missense_variant	17/43	1	NM_000037.4	A2	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

GnomAD3 exomes

AF:

0.0444

AC:

11169

AN:

251420

Hom.:

300

AF XY:

0.0409

AC XY:

5552

AN XY:

135910

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 SAS exome

AF:

0.0142

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

Gnomad4 AFR exome

AF:

0.0596

Gnomad4 AMR exome

AF:

0.0669

Gnomad4 ASJ exome

AF:

0.0262

Gnomad4 EAS exome

AF:

0.0473

Gnomad4 SAS exome

AF:

0.0151

Gnomad4 FIN exome

AF:

0.0395

Gnomad4 NFE exome

AF:

0.0536

Gnomad4 OTH exome

AF:

0.0433

GnomAD4 genome

AF:

0.0472

AC:

7183

AN:

152240

Hom.:

202

Cov.:

AF XY:

0.0454

AC XY:

3379

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0547

Gnomad4 AMR

AF:

0.0410

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.0369

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.0408

Gnomad4 NFE

AF:

0.0495

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0479

Hom.:

209

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
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	Nov 10, 2018	This variant is associated with the following publications: (PMID: 10745622) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Spherocytosis

Benign:1

Likely 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 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

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;.

MutationTaster

Benign

0.98

D;D;D;D;D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over