chr4-113345966-G-T

Variant names:

• chr4-113345966-G-T
• rs34591340
• NM_001148.6:c.4315G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001148.6(ANK2):​c.4315G>T​(p.Gly1439Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G1439V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4 O:1
• Conservation: PhyloP100: 2.89
• Publications: 11 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18178931).
• BP6: Variant 4-113345966-G-T is Benign according to our data. Variant chr4-113345966-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67606.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000223 (34/152300) while in subpopulation NFE AF = 0.000397 (27/68024). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 34 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.4315G>T	p.Gly1439Cys	missense	Exon 35 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.4456G>T	p.Gly1486Cys	missense	Exon 37 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.4432G>T	p.Gly1478Cys	missense	Exon 36 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.4315G>T	p.Gly1439Cys	missense	Exon 35 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.4456G>T	p.Gly1486Cys	missense	Exon 37 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4315G>T	p.Gly1439Cys	missense	Exon 35 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000397

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000283 AC: 71 AN: 251232 AF XY: 0.000324

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000332 AC: 485 AN: 1461436 Hom.: 0 Cov.: 33 AF XY: 0.000330 AC XY: 240 AN XY: 727054

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000399 AC: 444 AN: 1111660

Other (OTH) AF: 0.000248 AC: 15 AN: 60376

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74472

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15300

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: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Cardiac arrhythmia, ankyrin-B-related (4)
-	1	1	Cardiovascular phenotype (2)
-	2	-	not provided (3)
-	1	-	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.27
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.035	D
Polyphen		0.035	B
Vest4		0.69
MVP		0.86
MPC		1.4
ClinPred		0.17	T
GERP RS		6.1
Varity_R		0.71
gMVP		0.42
Mutation Taster		=44/56	disease causing

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: rs34591340; hg19: chr4-114267122; COSMIC: COSV99053407; COSMIC: COSV99053407;