4-112904665-A-T

Position:

• chr4-112904665-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000506722.5(ANK2):​c.21+151A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 152,264 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.019 (81 hom., cov: 33)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.211

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-112904665-A-T is Benign according to our data. Variant chr4-112904665-A-T is described in ClinVar as [Benign]. Clinvar id is 675525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001127493.3	c.21+151A>T		intron_variant			NP_001120965.1
ANK2	NM_001354239.2	c.21+151A>T		intron_variant			NP_001341168.1
ANK2	NM_001354243.2	c.21+151A>T		intron_variant			NP_001341172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.21+151A>T		intron_variant		1		ENSP00000421067
ANK2	ENST00000503271.5	c.21+151A>T		intron_variant		2		ENSP00000423799
ANK2	ENST00000503423.6	c.21+151A>T		intron_variant		5		ENSP00000421011	A2

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2927 AN: 152146 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.0134

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

GnomAD4 genome AF: 0.0192 AC: 2930 AN: 152264 Hom.: 81 Cov.: 33 AF XY: 0.0181 AC XY: 1351 AN XY: 74452

Gnomad4 AFR AF: 0.0653

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000677

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0157 Hom.: 5

Bravo AF: 0.0227

Asia WGS AF: 0.00262 AC: 9 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs112428084; hg19: chr4-113825821;