Genetic Variant ANK2:c.1881+8C>G (chr4-113278566-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001148.6(ANK2):c.1881+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,613,060 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 5 hom. )

Consequence

ANK2
NM_001148.6 splice_region, intron

Scores

Splicing: ADA: 0.0001745

Clinical Significance

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

Conservation

PhyloP100: 0.569

Publications

1 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=-0.67).

BP6

Variant 4-113278566-C-G is Benign according to our data. Variant chr4-113278566-C-G is described in ClinVar as Benign. ClinVar VariationId is 347309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00566 (862/152178) while in subpopulation AFR AF = 0.0197 (818/41516). AF 95% confidence interval is 0.0186. There are 7 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 862 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	Effect	Exon Rank	Protein	UniProt
ANK2	NM_001148.6	MANE Select	c.1881+8C>G	splice_region intron	N/A	NP_001139.3
ANK2	NM_001386174.1		c.1932+8C>G	splice_region intron	N/A	NP_001373103.1	H0Y933
ANK2	NM_001386175.1		c.1908+8C>G	splice_region intron	N/A	NP_001373104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANK2	ENST00000357077.9	TSL:1 MANE Select	c.1881+8C>G	splice_region intron	N/A	ENSP00000349588.4	Q01484-4
ANK2	ENST00000506344.6	TSL:1	c.1932+8C>G	splice_region intron	N/A	ENSP00000422888.2	H0Y933
ANK2	ENST00000394537.7	TSL:1	c.1881+8C>G	splice_region intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes

AF:

0.00567

AC:

862

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

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:

0.0000147

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00139

AC:

350

AN:

251282

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000483

AC:

705

AN:

1460882

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

293

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.0177

AC:

591

AN:

33460

American (AMR)

AF:

0.000827

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111152

Other (OTH)

AF:

0.00109

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00566

AC:

862

AN:

152178

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

417

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0197

AC:

818

AN:

41516

American (AMR)

AF:

0.00203

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

155

194

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:

0.00143

Hom.:

Bravo

AF:

0.00613

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiac arrhythmia, ankyrin-B-related (2)

not specified (2)

Long QT syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.4

(source)

DANN

Benign

0.79

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.012

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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