rs786205420

Variant names:

• chr4-113293537-C-T
• rs786205420
• NM_001148.6:c.2474C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001148.6(ANK2):​c.2474C>T​(p.Thr825Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000891 in 1,458,670 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense, splice_region
• Scores: Splicing: ADA: 0.9868
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.17
• Publications: 9 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 13 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.2474C>T	p.Thr825Ile	missense_variant, splice_region_variant	Exon 22 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.2474C>T	p.Thr825Ile	missense_variant, splice_region_variant	Exon 22 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458670 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725838

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110002

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000160 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Pathogenic:1

-

Medical Research Institute, Tokyo Medical and Dental University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;.;T;.;D;T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.1	.;.;.;.;M;M;.;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.48
Sift	Benign	0.064	T;T;T;T;T;D;D;.;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.78, 1.0	.;.;D;.;P;D;.;.;D
Vest4		0.63, 0.62, 0.68, 0.80, 0.62
MutPred		0.39		.;.;.;.;Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);.;.;
MVP		0.67
MPC		1.6
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.15	Neutral
Varity_R		0.67
gMVP		0.40
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
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

Other links and lift over

dbSNP: rs786205420; hg19: chr4-114214693;