rs2304871

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000037.4(ANK1):c.315C>T(p.Asn105Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,572 control chromosomes in the GnomAD database, including 58,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4494 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53628 hom. )

Consequence

ANK1
NM_000037.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.714

Publications

27 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 8-41727920-G-A is Benign according to our data. Variant chr8-41727920-G-A is described in ClinVar as Benign. ClinVar VariationId is 261304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.714 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.315C>T	p.Asn105Asn	synonymous_variant	Exon 4 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.315C>T	p.Asn105Asn	synonymous_variant	Exon 4 of 43	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36345

AN:

152010

Hom.:

4488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.182

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.258

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.241

AC:

60622

AN:

251384

AF XY:

0.249

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.268

AC:

391016

AN:

1461444

Hom.:

53628

Cov.:

AF XY:

0.269

AC XY:

195343

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.184

AC:

6166

AN:

33478

American (AMR)

AF:

0.147

AC:

6555

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

9002

AN:

26132

East Asian (EAS)

AF:

0.172

AC:

6824

AN:

39700

South Asian (SAS)

AF:

0.256

AC:

22053

AN:

86256

European-Finnish (FIN)

AF:

0.217

AC:

11580

AN:

53400

Middle Eastern (MID)

AF:

0.378

AC:

2180

AN:

5766

European-Non Finnish (NFE)

AF:

0.279

AC:

310264

AN:

1111604

Other (OTH)

AF:

0.271

AC:

16392

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

15196

30393

45589

60786

75982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10258

20516

30774

41032

51290

<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:

0.239

AC:

36357

AN:

152128

Hom.:

4494

Cov.:

AF XY:

0.236

AC XY:

17531

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.182

AC:

7544

AN:

41524

American (AMR)

AF:

0.227

AC:

3465

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

1177

AN:

3464

East Asian (EAS)

AF:

0.207

AC:

1070

AN:

5168

South Asian (SAS)

AF:

0.260

AC:

1255

AN:

4820

European-Finnish (FIN)

AF:

0.203

AC:

2146

AN:

10574

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18880

AN:

67978

Other (OTH)

AF:

0.259

AC:

547

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1407

2814

4220

5627

7034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

396

792

1188

1584

1980

<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:

0.260

Hom.:

5343

Bravo

AF:

0.238

Asia WGS

AF:

0.232

AC:

806

AN:

3478

EpiCase

AF:

0.292

EpiControl

AF:

0.296

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:5

Jan 13, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spherocytosis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.7

(source)

DANN

Benign

0.47

PhyloP100

-0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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