4-113354087-C-T

Variant names:

• chr4-113354087-C-T
• rs33966911
• NM_001148.6:c.5469C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001148.6(ANK2):​c.5469C>T​(p.Pro1823Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0959 in 1,613,984 control chromosomes in the GnomAD database, including 8,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (610 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7677 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.10
• Publications: 9 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: ClinGen, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• cardiac arrhythmia, ankyrin-B-related

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-113354087-C-T is Benign according to our data. Variant chr4-113354087-C-T is described in ClinVar as Benign. ClinVar VariationId is 257580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 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.5469C>T	p.Pro1823Pro	synonymous	Exon 38 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.5610C>T	p.Pro1870Pro	synonymous	Exon 40 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.5586C>T	p.Pro1862Pro	synonymous	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.5469C>T	p.Pro1823Pro	synonymous	Exon 38 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.5610C>T	p.Pro1870Pro	synonymous	Exon 40 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.4426+3838C>T		intron	N/A	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11493 AN: 152074 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0972

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.0793 AC: 19894 AN: 251024 AF XY: 0.0816

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0544

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0980 AC: 143328 AN: 1461792 Hom.: 7677 Cov.: 34 AF XY: 0.0973 AC XY: 70767 AN XY: 727190

African (AFR) AF: 0.0183 AC: 614 AN: 33476

American (AMR) AF: 0.0567 AC: 2536 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3004 AN: 26132

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.0307 AC: 2646 AN: 86258

European-Finnish (FIN) AF: 0.104 AC: 5565 AN: 53388

Middle Eastern (MID) AF: 0.129 AC: 741 AN: 5764

European-Non Finnish (NFE) AF: 0.110 AC: 122553 AN: 1111960

Other (OTH) AF: 0.0937 AC: 5657 AN: 60394

GnomAD4 genome AF: 0.0755 AC: 11484 AN: 152192 Hom.: 610 Cov.: 32 AF XY: 0.0729 AC XY: 5420 AN XY: 74396

African (AFR) AF: 0.0195 AC: 810 AN: 41554

American (AMR) AF: 0.0688 AC: 1051 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0231 AC: 111 AN: 4814

European-Finnish (FIN) AF: 0.0972 AC: 1031 AN: 10602

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7800 AN: 67982

Other (OTH) AF: 0.0981 AC: 207 AN: 2110

Alfa AF: 0.0999 Hom.: 444

Bravo AF: 0.0718

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.121

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.99
DANN	Benign	0.48
PhyloP100		-1.1
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: rs33966911; hg19: chr4-114275243; COSMIC: COSV108050251; COSMIC: COSV108050251;