rs864321653

chr4-113358861-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ANK2
• BP4: Computational evidence support a benign effect (MetaRNN=0.03730026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.10243A>G	p.Thr3415Ala	missense_variant	38/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.10243A>G	p.Thr3415Ala	missense_variant	38/46	1	NM_001148.6	A2

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

-

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;.;.
MutationTaster	Benign	0.76	D;D;D;D;N;N
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

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

LitVar

Other links and lift over

dbSNP: rs864321653; hg19: chr4-114280017;