NM_001148.6:c.3893+14G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001148.6(ANK2):c.3893+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,600,286 control chromosomes in the GnomAD database, including 17,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 5205 hom., cov: 32)

Exomes 𝑓: 0.11 ( 11826 hom. )

Consequence

ANK2
NM_001148.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.695

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-113339336-G-T is Benign according to our data. Variant chr4-113339336-G-T is described in ClinVar as Benign. ClinVar VariationId is 136391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001148.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ANK2	NM_001148.6	MANE Select	c.3893+14G>T	intron	N/A	NP_001139.3
ANK2	NM_001386174.1		c.4034+14G>T	intron	N/A	NP_001373103.1
ANK2	NM_001386175.1		c.4010+14G>T	intron	N/A	NP_001373104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ANK2	ENST00000357077.9	TSL:1 MANE Select	c.3893+14G>T	intron	N/A	ENSP00000349588.4
ANK2	ENST00000506344.6	TSL:1	c.4034+14G>T	intron	N/A	ENSP00000422888.2
ANK2	ENST00000394537.7	TSL:1	c.3893+14G>T	intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30931

AN:

152000

Hom.:

5181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.463

Gnomad AMI

AF:

0.0341

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.0971

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.0626

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.131

AC:

32906

AN:

251208

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.475

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.0987

Gnomad EAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.0616

Gnomad NFE exome

AF:

0.0999

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.112

AC:

161934

AN:

1448168

Hom.:

11826

Cov.:

AF XY:

0.112

AC XY:

80443

AN XY:

721434

show subpopulations

African (AFR)

AF:

0.477

AC:

15845

AN:

33234

American (AMR)

AF:

0.138

AC:

6163

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

2647

AN:

26034

East Asian (EAS)

AF:

0.125

AC:

4943

AN:

39600

South Asian (SAS)

AF:

0.126

AC:

10849

AN:

85970

European-Finnish (FIN)

AF:

0.0660

AC:

3517

AN:

53276

Middle Eastern (MID)

AF:

0.170

AC:

976

AN:

5740

European-Non Finnish (NFE)

AF:

0.0993

AC:

109175

AN:

1099650

Other (OTH)

AF:

0.130

AC:

7819

AN:

59956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

6433

12866

19300

25733

32166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4178

8356

12534

16712

20890

<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:

0.204

AC:

30999

AN:

152118

Hom.:

5205

Cov.:

AF XY:

0.199

AC XY:

14769

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.464

AC:

19220

AN:

41448

American (AMR)

AF:

0.148

AC:

2256

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0971

AC:

337

AN:

3470

East Asian (EAS)

AF:

0.117

AC:

604

AN:

5184

South Asian (SAS)

AF:

0.119

AC:

573

AN:

4820

European-Finnish (FIN)

AF:

0.0626

AC:

663

AN:

10586

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.101

AC:

6894

AN:

68006

Other (OTH)

AF:

0.181

AC:

381

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1065

2130

3196

4261

5326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.166

Hom.:

1300

Bravo

AF:

0.222

Asia WGS

AF:

0.142

AC:

492

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jun 14, 2012

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiac arrhythmia, ankyrin-B-related

Benign:2

Dec 05, 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:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Long QT syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.0

(source)

DANN

Benign

0.42

PhyloP100

0.69

Mutation Taster

=100/0

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

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