rs147706514

Variant names:

• chr4-113353849-C-A
• rs147706514
• NM_001148.6:c.5231C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-113353849-C-A
• chr4-113353849-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001148.6(ANK2):​c.5231C>A​(p.Ala1744Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1744T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.06
• Publications: 5 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16315034).
• BP6: Variant 4-113353849-C-A is Benign according to our data. Variant chr4-113353849-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264303.
• BS2: High AC in GnomAd4 at 14 AD,Unknown gene.

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.5231C>A	p.Ala1744Asp	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.5372C>A	p.Ala1791Asp	missense	Exon 40 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.5348C>A	p.Ala1783Asp	missense	Exon 39 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.5231C>A	p.Ala1744Asp	missense	Exon 38 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.5372C>A	p.Ala1791Asp	missense	Exon 40 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4426+3600C>A		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000720 AC: 18 AN: 249916 AF XY: 0.0000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461632 Hom.: 0 Cov.: 33 AF XY: 0.0000963 AC XY: 70 AN XY: 727116

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1111934

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Intellectual disability (1)
-	1	-	Long QT syndrome (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.29	T
Vest4		0.26
MVP		0.46
MPC		0.27
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.15
Mutation Taster		=89/11	polymorphism

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: rs147706514; hg19: chr4-114275005;