chr4-113358472-T-C

Variant names:

• chr4-113358472-T-C
• rs36210417
• NM_001148.6:c.9854T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001386174.1(ANK2):​c.9995T>C​(p.Ile3332Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00848 in 1,614,066 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3332L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (95 hom.)
• Consequence: ANK2 NM_001386174.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 4.70
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010287136).
• BP6: Variant 4-113358472-T-C is Benign according to our data. Variant chr4-113358472-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0081 (1234/152274) while in subpopulation AMR AF = 0.0157 (240/15284). AF 95% confidence interval is 0.0141. There are 6 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1234 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	NM_001148.6	MANE Select	c.9854T>C	p.Ile3285Thr	missense	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.9995T>C	p.Ile3332Thr	missense	Exon 40 of 51	NP_001373103.1
	ANK2	NM_001386175.1		c.9971T>C	p.Ile3324Thr	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.9854T>C	p.Ile3285Thr	missense	Exon 38 of 46	ENSP00000349588.4
	ANK2	ENST00000506344.6	TSL:1	c.9995T>C	p.Ile3332Thr	missense	Exon 40 of 51	ENSP00000422888.2
	ANK2	ENST00000394537.7	TSL:1	c.4427-2351T>C		intron	N/A	ENSP00000378044.3

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152156 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.00872 AC: 2184 AN: 250414 AF XY: 0.00905

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00874

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.00852 AC: 12453 AN: 1461792 Hom.: 95 Cov.: 34 AF XY: 0.00877 AC XY: 6381 AN XY: 727200

African (AFR) AF: 0.00167 AC: 56 AN: 33470

American (AMR) AF: 0.00919 AC: 411 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 732 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00497 AC: 429 AN: 86258

European-Finnish (FIN) AF: 0.00595 AC: 318 AN: 53416

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5764

European-Non Finnish (NFE) AF: 0.00873 AC: 9709 AN: 1111942

Other (OTH) AF: 0.0101 AC: 611 AN: 60392

GnomAD4 genome AF: 0.00810 AC: 1234 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74448

African (AFR) AF: 0.00156 AC: 65 AN: 41558

American (AMR) AF: 0.0157 AC: 240 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 740 AN: 68016

Other (OTH) AF: 0.0147 AC: 31 AN: 2106

Alfa AF: 0.0108 Hom.: 59

Bravo AF: 0.00911

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00820 AC: 996

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0124

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Cardiac arrhythmia, ankyrin-B-related (4)
-	-	4	not provided (4)
-	-	1	Atrial fibrillation;C0878544:Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.028	D
Vest4		0.86
MVP		0.97
MPC		0.50
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.077
Mutation Taster		=80/20	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: rs36210417; hg19: chr4-114279628;