rs1137177

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000037.4(ANK1):c.2073C>T(p.Gly691Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,702 control chromosomes in the GnomAD database, including 57,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4337 hom., cov: 33)

Exomes 𝑓: 0.26 ( 52879 hom. )

Consequence

ANK1
NM_000037.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.04

Publications

17 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.091).

BP6

Variant 8-41706167-G-A is Benign according to our data. Variant chr8-41706167-G-A is described in ClinVar as Benign. ClinVar VariationId is 261297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK1	NM_000037.4 link	c.2073C>T	p.Gly691Gly	synonymous_variant	Exon 18 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.2073C>T	p.Gly691Gly	synonymous_variant	Exon 18 of 43	1	NM_000037.4	ENSP00000289734.8		P16157-3

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31998

AN:

152086

Hom.:

4332

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0550

Gnomad AMI

AF:

0.283

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.306

Gnomad EAS

AF:

0.0713

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.355

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.219

GnomAD2 exomes

AF:

0.259

AC:

64990

AN:

251096

AF XY:

0.264

show subpopulations

Gnomad AFR exome

AF:

0.0489

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.319

Gnomad EAS exome

AF:

0.0680

Gnomad FIN exome

AF:

0.349

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.263

AC:

383995

AN:

1461498

Hom.:

52879

Cov.:

AF XY:

0.265

AC XY:

192847

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.0463

AC:

1550

AN:

33468

American (AMR)

AF:

0.291

AC:

13000

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

8038

AN:

26130

East Asian (EAS)

AF:

0.0824

AC:

3272

AN:

39700

South Asian (SAS)

AF:

0.315

AC:

27163

AN:

86242

European-Finnish (FIN)

AF:

0.343

AC:

18316

AN:

53368

Middle Eastern (MID)

AF:

0.257

AC:

1476

AN:

5754

European-Non Finnish (NFE)

AF:

0.266

AC:

295654

AN:

1111754

Other (OTH)

AF:

0.257

AC:

15526

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15705

31409

47114

62818

78523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9762

19524

29286

39048

48810

<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:

0.210

AC:

32005

AN:

152204

Hom.:

4337

Cov.:

AF XY:

0.214

AC XY:

15932

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0549

AC:

2280

AN:

41566

American (AMR)

AF:

0.258

AC:

3945

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

1061

AN:

3470

East Asian (EAS)

AF:

0.0710

AC:

367

AN:

5166

South Asian (SAS)

AF:

0.310

AC:

1493

AN:

4820

European-Finnish (FIN)

AF:

0.355

AC:

3761

AN:

10602

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.269

AC:

18305

AN:

67974

Other (OTH)

AF:

0.220

AC:

465

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1183

2366

3549

4732

5915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.242

Hom.:

8995

Bravo

AF:

0.195

Asia WGS

AF:

0.221

AC:

767

AN:

3478

EpiCase

AF:

0.270

EpiControl

AF:

0.266

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 1

Benign:3

Nov 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.79

CADD

Benign

2.1

(source)

DANN

Benign

0.46

PhyloP100

-2.0

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

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