4-112904713-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000506722.5(ANK2):c.21+199T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 151,954 control chromosomes in the GnomAD database, including 7,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (7299 hom., cov: 32)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.504

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-112904713-T-C is Benign according to our data. Variant chr4-112904713-T-C is described in ClinVar as [Benign]. Clinvar id is 672177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001127493.3	c.21+199T>C		intron_variant
ANK2	NM_001354239.2	c.21+199T>C		intron_variant
ANK2	NM_001354243.2	c.21+199T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000506722.5	c.21+199T>C		intron_variant		1
ANK2	ENST00000503271.5	c.21+199T>C		intron_variant		2
ANK2	ENST00000503423.6	c.21+199T>C		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40056 AN: 151836 Hom.: 7275 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.264 AC: 40127 AN: 151954 Hom.: 7299 Cov.: 32 AF XY: 0.257 AC XY: 19089 AN XY: 74292

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0821

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.275

Alfa AF: 0.194 Hom.: 4216

Bravo AF: 0.292

Asia WGS AF: 0.139 AC: 481 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.8
Dann	Benign	0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7675254; hg19: chr4-113825869;