rs35728190

Variant names:

• chr4-113363489-C-T
• rs35728190
• NM_001148.6:c.10888+20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001148.6(ANK2):​c.10888+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,242 control chromosomes in the GnomAD database, including 9,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (923 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8362 hom.)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.838
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-113363489-C-T is Benign according to our data. Variant chr4-113363489-C-T is described in ClinVar as Benign. ClinVar VariationId is 136394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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.10888+20C>T		intron	N/A	NP_001139.3
	ANK2	NM_001386174.1		c.11029+20C>T		intron	N/A	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.11005+20C>T		intron	N/A	NP_001373104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.10888+20C>T		intron	N/A	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.11029+20C>T		intron	N/A	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4633+20C>T		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16000 AN: 152056 Hom.: 923 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0874

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.0896 AC: 22487 AN: 251068 AF XY: 0.0901

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.103 AC: 150601 AN: 1460068 Hom.: 8362 Cov.: 32 AF XY: 0.102 AC XY: 74297 AN XY: 726374

African (AFR) AF: 0.119 AC: 3976 AN: 33398

American (AMR) AF: 0.0641 AC: 2863 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3108 AN: 26066

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39654

South Asian (SAS) AF: 0.0356 AC: 3069 AN: 86230

European-Finnish (FIN) AF: 0.106 AC: 5622 AN: 53256

Middle Eastern (MID) AF: 0.161 AC: 924 AN: 5756

European-Non Finnish (NFE) AF: 0.112 AC: 124779 AN: 1110754

Other (OTH) AF: 0.104 AC: 6248 AN: 60282

GnomAD4 genome AF: 0.105 AC: 16008 AN: 152174 Hom.: 923 Cov.: 32 AF XY: 0.103 AC XY: 7637 AN XY: 74406

African (AFR) AF: 0.114 AC: 4716 AN: 41502

American (AMR) AF: 0.0872 AC: 1333 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4830

European-Finnish (FIN) AF: 0.0996 AC: 1055 AN: 10594

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8023 AN: 67998

Other (OTH) AF: 0.121 AC: 256 AN: 2114

Alfa AF: 0.111 Hom.: 346

Bravo AF: 0.106

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Cardiac arrhythmia, ankyrin-B-related (2)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.099
DANN	Benign	0.20
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs35728190; hg19: chr4-114284645;