rs1137177

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000037.4(ANK1):c.2073C>T(p.Gly691=) 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:7

Conservation

PhyloP100: -2.04

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

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

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/exons	MANE	UniProt
ANK1	NM_000037.4 linkuse as main transcript	c.2073C>T	p.Gly691=	synonymous_variant	18/43	ENST00000289734.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK1	ENST00000289734.13 linkuse as main transcript	c.2073C>T	p.Gly691=	synonymous_variant	18/43	1	NM_000037.4	A2	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

GnomAD3 exomes

AF:

0.259

AC:

64990

AN:

251096

Hom.:

9407

AF XY:

0.264

AC XY:

35886

AN XY:

135734

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 SAS exome

AF:

0.320

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

Gnomad4 AFR exome

AF:

0.0463

Gnomad4 AMR exome

AF:

0.291

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.0824

Gnomad4 SAS exome

AF:

0.315

Gnomad4 FIN exome

AF:

0.343

Gnomad4 NFE exome

AF:

0.266

Gnomad4 OTH exome

AF:

0.257

GnomAD4 genome

AF:

0.210

AC:

32005

AN:

152204

Hom.:

4337

Cov.:

AF XY:

0.214

AC XY:

15932

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0549

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.306

Gnomad4 EAS

AF:

0.0710

Gnomad4 SAS

AF:

0.310

Gnomad4 FIN

AF:

0.355

Gnomad4 NFE

AF:

0.269

Gnomad4 OTH

AF:

0.220

Alfa

AF:

0.248

Hom.:

6883

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: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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Spherocytosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

Cadd

Benign

2.1

Dann

Benign

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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