rs61735313

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000037.4(ANK1):c.654C>A(p.Asn218Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0172 in 1,602,132 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 32)

Exomes 𝑓: 0.018 ( 284 hom. )

Consequence

ANK1
NM_000037.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.61

Publications

13 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=0.009991944).

BP6

Variant 8-41724513-G-T is Benign according to our data. Variant chr8-41724513-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261321.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 = 0.0123 (1878/152324) while in subpopulation NFE AF = 0.0204 (1391/68034). AF 95% confidence interval is 0.0196. There are 18 homozygotes in GnomAd4. There are 820 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.654C>A	p.Asn218Lys	missense_variant	Exon 7 of 43	ENST00000289734.13	NP_000028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK1	ENST00000289734.13 link	c.654C>A	p.Asn218Lys	missense_variant	Exon 7 of 43	1	NM_000037.4	ENSP00000289734.8

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1878

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00342

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0204

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0115

AC:

2651

AN:

229782

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00360

Gnomad AMR exome

AF:

0.00595

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00443

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0177

AC:

25716

AN:

1449808

Hom.:

284

Cov.:

AF XY:

0.0172

AC XY:

12346

AN XY:

719822

show subpopulations

African (AFR)

AF:

0.00342

AC:

114

AN:

33320

American (AMR)

AF:

0.00643

AC:

278

AN:

43268

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

324

AN:

25834

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39390

South Asian (SAS)

AF:

0.00324

AC:

271

AN:

83730

European-Finnish (FIN)

AF:

0.00644

AC:

338

AN:

52446

Middle Eastern (MID)

AF:

0.0159

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.0212

AC:

23476

AN:

1106268

Other (OTH)

AF:

0.0138

AC:

825

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1441

2882

4322

5763

7204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.0123

AC:

1878

AN:

152324

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

820

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00341

AC:

142

AN:

41582

American (AMR)

AF:

0.0102

AC:

156

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00584

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0204

AC:

1391

AN:

68034

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0184

Hom.:

Bravo

AF:

0.0122

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0186

AC:

160

ExAC

AF:

0.0108

AC:

1305

Asia WGS

AF:

0.00289

AC:

AN:

3478

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

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 29, 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

- -

not specified

Benign:1

Apr 26, 2016

PreventionGenetics, part of Exact Sciences

Significance: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

Pathogenic

0.99

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.76

N;N;.

PhyloP100

3.6

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.77

MutPred

0.67

Gain of ubiquitination at N218 (P = 0.0494);Gain of ubiquitination at N218 (P = 0.0494);.;

MPC

2.0

ClinPred

0.031

GERP RS

5.5

Varity_R

0.77

gMVP

0.89

Mutation Taster

=97/3

polymorphism

(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