dbSNP rs72544141: ANK2:p.Glu1458Gly (chr4-113348277-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 4P and 13B. PS3BP4_StrongBP6BS1BS2

The NM_001148.6(ANK2):c.4373A>G(p.Glu1458Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,613,402 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000245576: "In vitro and in vivo functional studies in mice provide some evidence that the p.Glu1458Gly variant may impact protein function (Mohler 2003, Mohler 2004, Le Scouarnec 2008)."".

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

ANK2
NM_001148.6 missense, splice_region

Scores

Splicing: ADA: 0.7324

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:4O:1

Conservation

PhyloP100: 9.04

Publications

51 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 -9 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000245576: "In vitro and in vivo functional studies in mice provide some evidence that the p.Glu1458Gly variant may impact protein function (Mohler 2003, Mohler 2004, Le Scouarnec 2008)."

BP4

Computational evidence support a benign effect (MetaRNN=0.01375708).

BP6

Variant 4-113348277-A-G is Benign according to our data. Variant chr4-113348277-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18056.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000841 (128/152230) while in subpopulation AMR AF = 0.00334 (51/15282). AF 95% confidence interval is 0.00261. There are 1 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 128 AD,Unknown gene.

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.4373A>G	p.Glu1458Gly	missense splice_region	Exon 36 of 46	NP_001139.3
ANK2	NM_001386174.1		c.4514A>G	p.Glu1505Gly	missense splice_region	Exon 38 of 51	NP_001373103.1	H0Y933
ANK2	NM_001386175.1		c.4490A>G	p.Glu1497Gly	missense splice_region	Exon 37 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.4373A>G	p.Glu1458Gly	missense splice_region	Exon 36 of 46	ENSP00000349588.4	Q01484-4
ANK2	ENST00000506344.6	TSL:1	c.4514A>G	p.Glu1505Gly	missense splice_region	Exon 38 of 51	ENSP00000422888.2	H0Y933
ANK2	ENST00000394537.7	TSL:1	c.4373A>G	p.Glu1458Gly	missense splice_region	Exon 36 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000546

AC:

137

AN:

251086

AF XY:

0.000538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000802

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000735

AC:

1074

AN:

1461172

Hom.:

Cov.:

AF XY:

0.000718

AC XY:

522

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33444

American (AMR)

AF:

0.00179

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000850

AC:

945

AN:

1111512

Other (OTH)

AF:

0.000696

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000841

AC:

128

AN:

152230

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41552

American (AMR)

AF:

0.00334

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000941

AC:

AN:

67994

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000744

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiac arrhythmia, ankyrin-B-related (3)

Long QT syndrome (2)

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Conduction disorder of the heart (1)

Long QT syndrome 4 (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.016

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

PhyloP100

9.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.31

Sift

Benign

0.35

Sift4G

Benign

0.42

Polyphen

0.012

Vest4

0.55

MVP

0.62

MPC

1.0

ClinPred

0.13

GERP RS

5.7

Varity_R

0.52

gMVP

0.29

Mutation Taster

=43/57

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.73

Splicevardb

3.0

SpliceAI score (max)

0.070

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