4-113363442-C-G

Variant names:

• chr4-113363442-C-G
• rs45570339
• NM_001148.6:c.10861C>G

Variant summary

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

The NM_001386174.1(ANK2):​c.11002C>G​(p.Leu3668Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,430 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). Synonymous variant affecting the same amino acid position (i.e. L3668L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: ANK2 NM_001386174.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10 O:1
• Conservation: PhyloP100: 0.717
• Publications: 10 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=0.009227902).
• BP6: Variant 4-113363442-C-G is Benign according to our data. Variant chr4-113363442-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67597.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.003 (457/152216) while in subpopulation AFR AF = 0.0106 (440/41530). AF 95% confidence interval is 0.00978. There are 0 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 457 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386174.1. 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.10861C>G	p.Leu3621Val	missense	Exon 40 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.11002C>G	p.Leu3668Val	missense	Exon 42 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.10978C>G	p.Leu3660Val	missense	Exon 41 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.10861C>G	p.Leu3621Val	missense	Exon 40 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.11002C>G	p.Leu3668Val	missense	Exon 42 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.4606C>G	p.Leu1536Val	missense	Exon 39 of 45	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

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: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000669 AC: 168 AN: 251060 AF XY: 0.000516

Gnomad AFR exome AF: 0.00923

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1461214 Hom.: 3 Cov.: 31 AF XY: 0.000230 AC XY: 167 AN XY: 726914

African (AFR) AF: 0.0105 AC: 350 AN: 33428

American (AMR) AF: 0.000492 AC: 22 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111590

Other (OTH) AF: 0.000613 AC: 37 AN: 60340

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74408

African (AFR) AF: 0.0106 AC: 440 AN: 41530

American (AMR) AF: 0.000851 AC: 13 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000804 Hom.: 0

Bravo AF: 0.00324

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000857 AC: 104

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	Long QT syndrome (2)
-	-	2	not specified (2)
-	-	1	Cardiac arrhythmia, ankyrin-B-related (1)
-	-	1	Cardiovascular phenotype (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.049	D
MutationAssessor	Benign	0.26	N
PhyloP100		0.72
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.54
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0090	B
Vest4		0.27
MVP		0.95
MPC		0.44
ClinPred		0.0087	T
GERP RS		4.5
Varity_R		0.043
gMVP		0.31
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45570339; hg19: chr4-114284598; COSMIC: COSV100005116; COSMIC: COSV100005116;