rs17045935

chr4-113333413-T-C

Variant summary

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

The NM_001148.6(ANK2):c.3379+205T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 151,898 control chromosomes in the GnomAD database, including 8,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (8106 hom., cov: 31)
• Consequence: ANK2 NM_001148.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.66

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=-0.93).
• BP6: Variant 4-113333413-T-C is Benign according to our data. Variant chr4-113333413-T-C is described in ClinVar as [Benign]. Clinvar id is 672184.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK2	NM_001148.6	c.3379+205T>C		intron_variant		ENST00000357077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK2	ENST00000357077.9	c.3379+205T>C		intron_variant		1	NM_001148.6	A2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36615 AN: 151780 Hom.: 8077 Cov.: 31

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.213

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

GnomAD4 genome AF: 0.242 AC: 36694 AN: 151898 Hom.: 8106 Cov.: 31 AF XY: 0.237 AC XY: 17571 AN XY: 74274

Gnomad4 AFR AF: 0.594

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.0971

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0617

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.209

Alfa AF: 0.138 Hom.: 1422

Bravo AF: 0.265

Asia WGS AF: 0.159 AC: 553 AN: 3478

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	-0.93
Cadd	Benign	0.47
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs17045935; hg19: chr4-114254569;