dbSNP rs35446871: ANK2:p.Ile4130Ile (chr4-113381478-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The ENST00000506344.6(ANK2):c.12390C>T(p.Ile4130Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,614,054 control chromosomes in the GnomAD database, including 877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 86 hom., cov: 33)

Exomes 𝑓: 0.031 ( 791 hom. )

Consequence

ANK2
ENST00000506344.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.423

Publications

5 publications found

Variant links:

Genes affected

ANK2 (HGNC:493): (ankyrin 2) This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. 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. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]

ANK2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P
cardiac arrhythmia, ankyrin-B-related
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ANK2 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=0.132).

BP6

Variant 4-113381478-C-T is Benign according to our data. Variant chr4-113381478-C-T is described in ClinVar as Benign. ClinVar VariationId is 136400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.423 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0297 (4522/152294) while in subpopulation NFE AF = 0.033 (2243/68028). AF 95% confidence interval is 0.0318. There are 86 homozygotes in GnomAd4. There are 2178 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4522 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000506344.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANK2	NM_001148.6	MANE Select	c.*7C>T		3_prime_UTR	Exon 46 of 46	NP_001139.3
ANK2	NM_001386174.1		c.12390C>T	p.Ile4130Ile	synonymous	Exon 51 of 51	NP_001373103.1
ANK2	NM_001386175.1		c.12366C>T	p.Ile4122Ile	synonymous	Exon 50 of 50	NP_001373104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANK2	ENST00000506344.6	TSL:1	c.12390C>T	p.Ile4130Ile	synonymous	Exon 51 of 51	ENSP00000422888.2
ANK2	ENST00000514167.1	TSL:1	c.204C>T	p.Ile68Ile	synonymous	Exon 3 of 3	ENSP00000422486.1
ANK2	ENST00000357077.9	TSL:1 MANE Select	c.*7C>T		3_prime_UTR	Exon 46 of 46	ENSP00000349588.4

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4519

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0276

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0282

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0330

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0330

Gnomad OTH

AF:

0.0382

GnomAD2 exomes

AF:

0.0280

AC:

7035

AN:

251000

AF XY:

0.0274

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.0216

Gnomad ASJ exome

AF:

0.0496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0355

Gnomad NFE exome

AF:

0.0370

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0311

AC:

45401

AN:

1461760

Hom.:

791

Cov.:

AF XY:

0.0306

AC XY:

22287

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0284

AC:

951

AN:

33480

American (AMR)

AF:

0.0226

AC:

1012

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

1326

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.00641

AC:

553

AN:

86254

European-Finnish (FIN)

AF:

0.0361

AC:

1926

AN:

53408

Middle Eastern (MID)

AF:

0.0291

AC:

168

AN:

5768

European-Non Finnish (NFE)

AF:

0.0338

AC:

37624

AN:

1111924

Other (OTH)

AF:

0.0305

AC:

1839

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

2460

4920

7379

9839

12299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1386

2772

4158

5544

6930

<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:

0.0297

AC:

4522

AN:

152294

Hom.:

Cov.:

AF XY:

0.0292

AC XY:

2178

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0275

AC:

1144

AN:

41552

American (AMR)

AF:

0.0282

AC:

431

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0330

AC:

351

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0330

AC:

2243

AN:

68028

Other (OTH)

AF:

0.0378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

232

463

695

926

1158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0318

Hom.:

Bravo

AF:

0.0304

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0347

EpiControl

AF:

0.0357

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 10, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiac arrhythmia, ankyrin-B-related

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.7

(source)

DANN

Benign

0.60

PhyloP100

-0.42

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over