4-113049776-C-G

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.48C>G(p.Phe16Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F16F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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-AS1 (HGNC:40076): (ANK2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. 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=0.105382055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.48C>G	p.Phe16Leu	missense_variant	1/46	ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.48C>G	p.Phe16Leu	missense_variant	1/46	1	NM_001148.6	A2
ANK2-AS1	ENST00000508959.1	n.126-14982G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2023

The p.F16L variant (also known as c.48C>G), located in coding exon 1 of the ANK2 gene, results from a C to G substitution at nucleotide position 48. The phenylalanine at codon 16 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.87
DEOGEN2	Benign	0.22	T;.;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.0, 0.58	.;B;P;.
Vest4		0.24, 0.24, 0.30
MutPred		0.27		Gain of glycosylation at S20 (P = 0.0016);Gain of glycosylation at S20 (P = 0.0016);Gain of glycosylation at S20 (P = 0.0016);Gain of glycosylation at S20 (P = 0.0016);
MVP		0.62
MPC		0.67
ClinPred		0.25	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-113970932;