chr4-113355151-TT-AC

Variant names:

• chr4-113355151-TT-AC
• NM_001148.6:c.6533_6534delTTinsAC
• ANK2 p.Phe2178Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001148.6(ANK2):c.6533_6534delTTinsAC (p.Phe2178Tyr) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F2178Y: Uncertain_significance (ClinVar VariationId 191409, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• 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, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, PanelApp Australia
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, G2P, Genomics England PanelApp
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, G2P, Genomics England PanelApp
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P, ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001148.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ANK2 NM_001148.6	MANE Select	c.6533_6534delTTinsAC p.Phe2178Tyr	missense	N/A	Prot: NP_001139.3
	ANK2 NM_001386174.1		c.6674_6675delTTinsAC p.Phe2225Tyr	missense	N/A	Prot: NP_001373103.1 UniProt:
	ANK2 NM_001386175.1		c.6650_6651delTTinsAC p.Phe2217Tyr	missense	N/A	Prot: NP_001373104.1

ANK2 NM_001148.6

MANE Select

HGVSc / HGVSpc.6533_6534delTTinsACp.Phe2178Tyr

Exon rankN/A

missense

Prot: NP_001139.3

ANK2 NM_001386174.1

HGVSc / HGVSpc.6674_6675delTTinsACp.Phe2225Tyr

Exon rankN/A

missense

Prot: NP_001373103.1UniProt: H0Y933

ANK2 NM_001386175.1

HGVSc / HGVSpc.6650_6651delTTinsACp.Phe2217Tyr

Exon rankN/A

missense

Prot: NP_001373104.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ANK2 ENST00000357077.9	TSL:1MANE Select	c.6533_6534delTTinsAC p.Phe2178Tyr	missense	N/A	Prot: ENSP00000349588.4 UniProt:
	ANK2 ENST00000506344.6	TSL:1	c.6674_6675delTTinsAC p.Phe2225Tyr	missense	N/A	Prot: ENSP00000422888.2 UniProt:
	ANK2 ENST00000394537.7	TSL:1	c.4426+4902_4426+4903delTTinsAC	intron	Intron 37 of 44	Prot: ENSP00000378044.3 UniProt:

ANK2 ENST00000357077.9

TSL:1MANE Select

HGVSc / HGVSpc.6533_6534delTTinsACp.Phe2178Tyr

Exon rankN/A

missense

Prot: ENSP00000349588.4UniProt: Q01484-4

ANK2 ENST00000506344.6

TSL:1

HGVSc / HGVSpc.6674_6675delTTinsACp.Phe2225Tyr

Exon rankN/A

missense

Prot: ENSP00000422888.2UniProt: H0Y933

ANK2 ENST00000394537.7

TSL:1

HGVSc / HGVSpc.4426+4902_4426+4903delTTinsAC

Exon rankIntron 37 of 44

intron

Prot: ENSP00000378044.3UniProt: Q01484-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr4-114276307;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar