rs114896457

Variant names:

• chr4-113333195-C-A
• rs114896457
• NM_001148.6:c.3366C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-113333195-C-A
• chr4-113333195-C-G
• chr4-113333195-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001148.6(ANK2):​c.3366C>A​(p.Asn1122Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1122N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK2	NM_001148.6	c.3366C>A	p.Asn1122Lys	missense_variant	Exon 29 of 46	ENST00000357077.9	NP_001139.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000357077.9	c.3366C>A	p.Asn1122Lys	missense_variant	Exon 29 of 46	1	NM_001148.6	ENSP00000349588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.35
DANN	Benign	0.95
DEOGEN2	Benign	0.38	.;T;.;T;.;D;T;T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	.;.;.;.;M;M;.;.;.
PhyloP100		-1.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.97, 1.0	.;.;D;.;D;.;.;.;D
Vest4		0.92, 0.86, 0.83, 0.87, 0.84
MVP		0.82
MPC		1.6
ClinPred		0.98	D
GERP RS		-9.8
PromoterAI		-0.027	Neutral
Varity_R		0.83
gMVP		0.86
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114896457; hg19: chr4-114254351;