rs29305

Variant names:

• chr4-113295768-C-T
• rs29305
• NM_001148.6:c.2475+2230C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001148.6(ANK2):​c.2475+2230C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 151,992 control chromosomes in the GnomAD database, including 18,060 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18060 hom., cov: 32)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.483
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.2475+2230C>T		intron	N/A	NP_001139.3
	ANK2	NM_001386174.1		c.2526+2230C>T		intron	N/A	NP_001373103.1
	ANK2	NM_001386175.1		c.2502+2230C>T		intron	N/A	NP_001373104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.2475+2230C>T		intron	N/A	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.2526+2230C>T		intron	N/A	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.2475+2230C>T		intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73382 AN: 151874 Hom.: 18043 Cov.: 32

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.478

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.483 AC: 73434 AN: 151992 Hom.: 18060 Cov.: 32 AF XY: 0.478 AC XY: 35536 AN XY: 74282

African (AFR) AF: 0.490 AC: 20318 AN: 41472

American (AMR) AF: 0.408 AC: 6241 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1623 AN: 3466

East Asian (EAS) AF: 0.229 AC: 1182 AN: 5164

South Asian (SAS) AF: 0.483 AC: 2332 AN: 4824

European-Finnish (FIN) AF: 0.473 AC: 4997 AN: 10554

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.519 AC: 35249 AN: 67920

Other (OTH) AF: 0.472 AC: 996 AN: 2110

Alfa AF: 0.498 Hom.: 75543

Bravo AF: 0.474

Asia WGS AF: 0.356 AC: 1238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.89
DANN	Benign	0.45
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs29305; hg19: chr4-114216924;