dbSNP rs3796928: ANK2:p.Leu2056Leu (chr4-113354786-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001148.6(ANK2):c.6168C>G(p.Leu2056Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,613,864 control chromosomes in the GnomAD database, including 4,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2082 hom., cov: 32)

Exomes 𝑓: 0.032 ( 2327 hom. )

Consequence

ANK2
NM_001148.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0800

Publications

9 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: ClinGen, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
cardiac arrhythmia, ankyrin-B-related
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 4-113354786-C-G is Benign according to our data. Variant chr4-113354786-C-G is described in ClinVar as Benign. ClinVar VariationId is 257581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.08 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 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	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK2	NM_001148.6	MANE Select	c.6168C>G	p.Leu2056Leu	synonymous	Exon 38 of 46	NP_001139.3
ANK2	NM_001386174.1		c.6309C>G	p.Leu2103Leu	synonymous	Exon 40 of 51	NP_001373103.1	H0Y933
ANK2	NM_001386175.1		c.6285C>G	p.Leu2095Leu	synonymous	Exon 39 of 50	NP_001373104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK2	ENST00000357077.9	TSL:1 MANE Select	c.6168C>G	p.Leu2056Leu	synonymous	Exon 38 of 46	ENSP00000349588.4	Q01484-4
ANK2	ENST00000506344.6	TSL:1	c.6309C>G	p.Leu2103Leu	synonymous	Exon 40 of 51	ENSP00000422888.2	H0Y933
ANK2	ENST00000394537.7	TSL:1	c.4426+4537C>G		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16018

AN:

152022

Hom.:

2079

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0561

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.0512

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0929

GnomAD2 exomes

AF:

0.0444

AC:

11128

AN:

250746

AF XY:

0.0392

show subpopulations

Gnomad AFR exome

AF:

0.315

Gnomad AMR exome

AF:

0.0277

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.0519

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0240

Gnomad OTH exome

AF:

0.0371

GnomAD4 exome

AF:

0.0317

AC:

46319

AN:

1461724

Hom.:

2327

Cov.:

AF XY:

0.0307

AC XY:

22333

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.314

AC:

10516

AN:

33464

American (AMR)

AF:

0.0314

AC:

1402

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

600

AN:

26134

East Asian (EAS)

AF:

0.0563

AC:

2233

AN:

39696

South Asian (SAS)

AF:

0.0236

AC:

2033

AN:

86236

European-Finnish (FIN)

AF:

0.0119

AC:

638

AN:

53414

Middle Eastern (MID)

AF:

0.0569

AC:

328

AN:

5762

European-Non Finnish (NFE)

AF:

0.0231

AC:

25674

AN:

1111920

Other (OTH)

AF:

0.0479

AC:

2895

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2619

5239

7858

10478

13097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1154

2308

3462

4616

5770

<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:

0.105

AC:

16044

AN:

152140

Hom.:

2082

Cov.:

AF XY:

0.102

AC XY:

7586

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.310

AC:

12862

AN:

41482

American (AMR)

AF:

0.0560

AC:

857

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3468

East Asian (EAS)

AF:

0.0511

AC:

264

AN:

5166

South Asian (SAS)

AF:

0.0172

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10610

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1578

AN:

67990

Other (OTH)

AF:

0.0915

AC:

193

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

600

1199

1799

2398

2998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<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:

0.0444

Hom.:

178

Bravo

AF:

0.117

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0257

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiac arrhythmia, ankyrin-B-related (2)

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.40

(source)

DANN

Benign

0.26

PhyloP100

0.080

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

Computational scores

Splicing

Publications

Other links and lift over