chr4-113282742-A-C

Position:

• chr4-113282742-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001148.6(ANK2):​c.1949A>C​(p.Asn650Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.370

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK2. . Gene score misZ 1.9641 (greater than the threshold 3.09). Trascript score misZ 4.2513 (greater than threshold 3.09). GenCC has associacion of gene with heart conduction disease, Brugada syndrome, long QT syndrome, complex neurodevelopmental disorder, cardiac arrhythmia, ankyrin-B-related, catecholaminergic polymorphic ventricular tachycardia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20928776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001148.6	c.1949A>C	p.Asn650Thr	missense_variant	18/46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.1949A>C	p.Asn650Thr	missense_variant	18/46	1	NM_001148.6	ENSP00000349588	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2020

This sequence change replaces asparagine with threonine at codon 650 of the ANK2 protein (p.Asn650Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ANK2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;.;T;.;T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;D;T;T;T;D;D;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	.;.;.;.;N;N;.;.
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;.
REVEL	Benign	0.045
Sift	Uncertain	0.013	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.038	D;D;D;D;D;D;D;D
Polyphen		0.036, 0.56, 0.15	.;.;B;.;P;B;.;.
Vest4		0.27, 0.27, 0.34, 0.29
MutPred		0.34		.;.;.;.;Loss of stability (P = 0.1293);Loss of stability (P = 0.1293);Loss of stability (P = 0.1293);.;
MVP		0.66
MPC		0.68
ClinPred		0.46	T
GERP RS		-1.3
Varity_R		0.44
gMVP		0.10

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: rs191468663; hg19: chr4-114203898;