chr4-113147771-G-C

Variant names:

• chr4-113147771-G-C
• rs1351998
• NM_001148.6:c.85-26645G>C

Variant summary

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

The NM_001148.6(ANK2):​c.85-26645G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 152,052 control chromosomes in the GnomAD database, including 17,568 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 0.47 (17568 hom., cov: 33)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 2 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 (AFR) allele frequency at 95% confidence interval = 0.621 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.85-26645G>C		intron	N/A	NP_001139.3
	ANK2	NM_001386174.1		c.135+1768G>C		intron	N/A	NP_001373103.1
	ANK2	NM_001386175.1		c.135+1768G>C		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.85-26645G>C		intron	N/A	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.135+1768G>C		intron	N/A	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.85-26645G>C		intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71151 AN: 151934 Hom.: 17524 Cov.: 33

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.469 AC: 71258 AN: 152052 Hom.: 17568 Cov.: 33 AF XY: 0.470 AC XY: 34915 AN XY: 74316

African (AFR) AF: 0.627 AC: 26026 AN: 41486

American (AMR) AF: 0.528 AC: 8064 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1045 AN: 3462

East Asian (EAS) AF: 0.512 AC: 2651 AN: 5174

South Asian (SAS) AF: 0.248 AC: 1195 AN: 4826

European-Finnish (FIN) AF: 0.461 AC: 4862 AN: 10542

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25964 AN: 67978

Other (OTH) AF: 0.452 AC: 957 AN: 2116

Alfa AF: 0.428 Hom.: 1802

Bravo AF: 0.488

Asia WGS AF: 0.399 AC: 1389 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.58
DANN	Benign	0.41
PhyloP100		-1.1
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: rs1351998; hg19: chr4-114068927;