chr4-113358861-A-G

Variant names:

• chr4-113358861-A-G
• rs864321653
• NM_001148.6:c.10243A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001148.6(ANK2):​c.10243A>G​(p.Thr3415Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3415R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03730026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.10243A>G	p.Thr3415Ala	missense_variant	Exon 38 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.10243A>G	p.Thr3415Ala	missense_variant	Exon 38 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital long QT syndrome Uncertain:1

-

Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While this variant hasn't been reported in any earlier clinical studies, several ANK2 variants have been associated with LQTS. ANK2 loss of function variants are known to interfere with the intermolecular interactions of ANK2 leading to mislocalization of ANK-associated membrane proteins, thereby disrupting cardiomyocyte excitability. In vitro analyses of various ANK2 variants associated with LQTS have revealed that loss of activity variants such as p.Gln1404Ile, p.Thr1552Asn and p.Thr1626Asn, retain normal localization of InsP(3) receptor and Na/Ca exchanger but causes abnormal contraction rates and aberrant spatial temporal pattern of calcium release; while the loss of function variants associated with LQTS such as p.Glu1425Gly, p.Val1516Asp and p.Arg1788Trp abolish localization of InsP(3) receptor and the Na/Ca exchanger and are associated with decreased contraction rates and more severe arrhythmia phenotypes in the patients [PMID:17242276]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.86
DANN	Benign	0.73
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.037	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.90	N;.;.
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.31	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.92	T;T;T
Sift4G	Benign	0.86	T;T;T
Vest4		0.045
MVP		0.44
MPC		0.077
ClinPred		0.031	T
GERP RS		-3.3
Varity_R		0.048
gMVP		0.059
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs864321653; hg19: chr4-114280017;