rs149645600

Variant names:

• chr4-113354824-G-A
• rs149645600
• NM_001148.6:c.6206G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-113354824-G-A
• chr4-113354824-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001148.6(ANK2):​c.6206G>A​(p.Arg2069His) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,614,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R2069C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 4.38
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016016811).
• BP6: Variant 4-113354824-G-A is Benign according to our data. Variant chr4-113354824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180270.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000663 (101/152326) while in subpopulation NFE AF = 0.00121 (82/68038). AF 95% confidence interval is 0.000994. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 101 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.6206G>A	p.Arg2069His	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.6347G>A	p.Arg2116His	missense	Exon 40 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.6323G>A	p.Arg2108His	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.6206G>A	p.Arg2069His	missense	Exon 38 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.6347G>A	p.Arg2116His	missense	Exon 40 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4426+4575G>A		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000697 AC: 175 AN: 250958 AF XY: 0.000656

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00110 AC: 1605 AN: 1461818 Hom.: 3 Cov.: 35 AF XY: 0.00105 AC XY: 766 AN XY: 727206

African (AFR) AF: 0.000269 AC: 9 AN: 33468

American (AMR) AF: 0.000268 AC: 12 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86250

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00137 AC: 1519 AN: 1111974

Other (OTH) AF: 0.000646 AC: 39 AN: 60390

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74478

African (AFR) AF: 0.000192 AC: 8 AN: 41578

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000982 Hom.: 0

Bravo AF: 0.000654

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000857 AC: 104

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Cardiac arrhythmia, ankyrin-B-related (2)
-	1	1	Long QT syndrome (2)
-	1	-	Cardiac arrest (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.0046
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D
Sift4G	Benign	0.10	T
Vest4		0.16
MVP		0.64
MPC		0.45
ClinPred		0.045	T
GERP RS		3.6
Varity_R		0.060
gMVP		0.026
Mutation Taster		=93/7	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: rs149645600; hg19: chr4-114275980;