rs10013743

Variant names:

• chr4-113358266-A-G
• rs10013743
• NM_001148.6:c.9648A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001148.6(ANK2):​c.9648A>G​(p.Glu3216Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,894 control chromosomes in the GnomAD database, including 10,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1317 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8796 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.254
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-113358266-A-G is Benign according to our data. Variant chr4-113358266-A-G is described in ClinVar as Benign. ClinVar VariationId is 257583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.254 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 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.9648A>G	p.Glu3216Glu	synonymous	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.9789A>G	p.Glu3263Glu	synonymous	Exon 40 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.9765A>G	p.Glu3255Glu	synonymous	Exon 39 of 50	NP_001373104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.9648A>G	p.Glu3216Glu	synonymous	Exon 38 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.9789A>G	p.Glu3263Glu	synonymous	Exon 40 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.4427-2557A>G		intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18687 AN: 152088 Hom.: 1315 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.0946 AC: 23708 AN: 250546 AF XY: 0.0936

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.105 AC: 154071 AN: 1461688 Hom.: 8796 Cov.: 35 AF XY: 0.104 AC XY: 75830 AN XY: 727140

African (AFR) AF: 0.185 AC: 6200 AN: 33464

American (AMR) AF: 0.0669 AC: 2992 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3122 AN: 26128

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39696

South Asian (SAS) AF: 0.0365 AC: 3147 AN: 86234

European-Finnish (FIN) AF: 0.107 AC: 5713 AN: 53406

Middle Eastern (MID) AF: 0.163 AC: 942 AN: 5762

European-Non Finnish (NFE) AF: 0.113 AC: 125402 AN: 1111898

Other (OTH) AF: 0.108 AC: 6541 AN: 60390

GnomAD4 genome AF: 0.123 AC: 18708 AN: 152206 Hom.: 1317 Cov.: 32 AF XY: 0.120 AC XY: 8894 AN XY: 74408

African (AFR) AF: 0.175 AC: 7251 AN: 41524

American (AMR) AF: 0.0939 AC: 1437 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 387 AN: 3470

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5164

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4828

European-Finnish (FIN) AF: 0.100 AC: 1064 AN: 10618

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8056 AN: 67982

Other (OTH) AF: 0.129 AC: 272 AN: 2112

Alfa AF: 0.124 Hom.: 1952

Bravo AF: 0.127

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.128

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cardiac arrhythmia, ankyrin-B-related (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.26
DANN	Benign	0.26
PhyloP100		0.25
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: rs10013743; hg19: chr4-114279422; COSMIC: COSV52165718; COSMIC: COSV52165718;