rs29341

Variant names:

• chr4-113292475-C-T
• rs29341
• NM_001148.6:c.2337C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001148.6(ANK2):​c.2337C>T​(p.Val779Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,611,660 control chromosomes in the GnomAD database, including 1,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (96 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1064 hom.)
• Consequence: ANK2 NM_001148.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.922
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-113292475-C-T is Benign according to our data. Variant chr4-113292475-C-T is described in ClinVar as Benign. ClinVar VariationId is 263475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.922 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0336 (5125/152352) while in subpopulation NFE AF = 0.0383 (2606/68038). AF 95% confidence interval is 0.0371. There are 96 homozygotes in GnomAd4. There are 2563 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5125 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.2337C>T	p.Val779Val	synonymous	Exon 21 of 46	NP_001139.3
	ANK2	NM_001386174.1		c.2388C>T	p.Val796Val	synonymous	Exon 21 of 51	NP_001373103.1	H0Y933
	ANK2	NM_001386175.1		c.2364C>T	p.Val788Val	synonymous	Exon 20 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.2337C>T	p.Val779Val	synonymous	Exon 21 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000506344.6	TSL:1	c.2388C>T	p.Val796Val	synonymous	Exon 21 of 51	ENSP00000422888.2	H0Y933
	ANK2	ENST00000394537.7	TSL:1	c.2337C>T	p.Val779Val	synonymous	Exon 21 of 45	ENSP00000378044.3	Q01484-2

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5122 AN: 152234 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0289 AC: 7068 AN: 244874 AF XY: 0.0291

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0353 AC: 51477 AN: 1459308 Hom.: 1064 Cov.: 32 AF XY: 0.0350 AC XY: 25434 AN XY: 725674

African (AFR) AF: 0.0274 AC: 914 AN: 33408

American (AMR) AF: 0.0205 AC: 913 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 394 AN: 26082

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39612

South Asian (SAS) AF: 0.0208 AC: 1779 AN: 85660

European-Finnish (FIN) AF: 0.0589 AC: 3136 AN: 53210

Middle Eastern (MID) AF: 0.0361 AC: 208 AN: 5764

European-Non Finnish (NFE) AF: 0.0381 AC: 42290 AN: 1110776

Other (OTH) AF: 0.0305 AC: 1840 AN: 60268

GnomAD4 genome AF: 0.0336 AC: 5125 AN: 152352 Hom.: 96 Cov.: 32 AF XY: 0.0344 AC XY: 2563 AN XY: 74506

African (AFR) AF: 0.0287 AC: 1195 AN: 41568

American (AMR) AF: 0.0316 AC: 484 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

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

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4830

European-Finnish (FIN) AF: 0.0559 AC: 594 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0383 AC: 2606 AN: 68038

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0345 Hom.: 97

Bravo AF: 0.0309

Asia WGS AF: 0.00837 AC: 29 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)
-	-	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	-0.45
CADD	Benign	9.0
DANN	Benign	0.90
PhyloP100		-0.92
PromoterAI		-0.097	Neutral
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: rs29341; hg19: chr4-114213631;