chr4-113145177-A-G

Variant names:

• chr4-113145177-A-G
• rs17579878
• NM_001148.6:c.85-29239A>G

Variant summary

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

The NM_001148.6(ANK2):​c.85-29239A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,104 control chromosomes in the GnomAD database, including 2,742 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 0.19 (2742 hom., cov: 32)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 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.85-29239A>G		intron	N/A	NP_001139.3
	ANK2	NM_001386142.1		c.22-29239A>G		intron	N/A	NP_001373071.1
	ANK2	NM_001386143.1		c.22-29239A>G		intron	N/A	NP_001373072.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.85-29239A>G		intron	N/A	ENSP00000349588.4
	ANK2	ENST00000394537.7	TSL:1	c.85-29239A>G		intron	N/A	ENSP00000378044.3
	ANK2	ENST00000506722.5	TSL:1	c.22-29239A>G		intron	N/A	ENSP00000421067.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28256 AN: 151986 Hom.: 2735 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.186 AC: 28293 AN: 152104 Hom.: 2742 Cov.: 32 AF XY: 0.183 AC XY: 13608 AN XY: 74376

African (AFR) AF: 0.228 AC: 9466 AN: 41482

American (AMR) AF: 0.112 AC: 1717 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3460

East Asian (EAS) AF: 0.107 AC: 552 AN: 5182

South Asian (SAS) AF: 0.159 AC: 768 AN: 4818

European-Finnish (FIN) AF: 0.194 AC: 2047 AN: 10578

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.188 AC: 12770 AN: 67974

Other (OTH) AF: 0.152 AC: 321 AN: 2114

Alfa AF: 0.179 Hom.: 7861

Bravo AF: 0.180

Asia WGS AF: 0.133 AC: 464 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.74
DANN	Benign	0.36
PhyloP100		0.077
PromoterAI		0.00030	Neutral
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: rs17579878; hg19: chr4-114066333; COSMIC: COSV107265902; COSMIC: COSV107265902;