rs2293324

Variant names:

• chr4-113373152-T-C
• rs2293324
• NM_001148.6:c.11673T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001148.6(ANK2):​c.11673T>C​(p.His3891His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,360 control chromosomes in the GnomAD database, including 35,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (10052 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24954 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.29
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.169).
• BP6: Variant 4-113373152-T-C is Benign according to our data. Variant chr4-113373152-T-C is described in ClinVar as Benign. ClinVar VariationId is 136397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.11673T>C	p.His3891His	synonymous	Exon 44 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.11907T>C	p.His3969His	synonymous	Exon 47 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.11883T>C	p.His3961His	synonymous	Exon 46 of 50	NP_001373104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.11673T>C	p.His3891His	synonymous	Exon 44 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.11907T>C	p.His3969His	synonymous	Exon 47 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.5418T>C	p.His1806His	synonymous	Exon 43 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44222 AN: 152028 Hom.: 10024 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.189 AC: 47434 AN: 251126 AF XY: 0.180

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.138

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.166 AC: 242218 AN: 1461214 Hom.: 24954 Cov.: 33 AF XY: 0.165 AC XY: 119619 AN XY: 726984

African (AFR) AF: 0.659 AC: 22045 AN: 33436

American (AMR) AF: 0.184 AC: 8217 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5334 AN: 26130

East Asian (EAS) AF: 0.141 AC: 5597 AN: 39692

South Asian (SAS) AF: 0.148 AC: 12744 AN: 86242

European-Finnish (FIN) AF: 0.123 AC: 6585 AN: 53418

Middle Eastern (MID) AF: 0.261 AC: 1503 AN: 5768

European-Non Finnish (NFE) AF: 0.152 AC: 168420 AN: 1111442

Other (OTH) AF: 0.195 AC: 11773 AN: 60362

GnomAD4 genome AF: 0.291 AC: 44293 AN: 152146 Hom.: 10052 Cov.: 32 AF XY: 0.285 AC XY: 21195 AN XY: 74398

African (AFR) AF: 0.637 AC: 26425 AN: 41476

American (AMR) AF: 0.208 AC: 3187 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3468

East Asian (EAS) AF: 0.136 AC: 702 AN: 5176

South Asian (SAS) AF: 0.134 AC: 646 AN: 4822

European-Finnish (FIN) AF: 0.117 AC: 1239 AN: 10600

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10708 AN: 67998

Other (OTH) AF: 0.279 AC: 590 AN: 2114

Alfa AF: 0.210 Hom.: 7444

Bravo AF: 0.317

Asia WGS AF: 0.166 AC: 576 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Cardiac arrhythmia, ankyrin-B-related (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.017
DANN	Benign	0.41
PhyloP100		-2.3
PromoterAI		-0.0022	Neutral
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2293324; hg19: chr4-114294308; COSMIC: COSV52180995; COSMIC: COSV52180995;