rs12500579

Positions:

• chr4-112934321-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000506722.5(ANK2):​c.21+29807C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,060 control chromosomes in the GnomAD database, including 2,050 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (2050 hom., cov: 32)
• Consequence: ANK2 ENST00000506722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK2	NM_001127493.3	c.21+29807C>G		intron_variant			NP_001120965.1
ANK2	NM_001354239.2	c.21+29807C>G		intron_variant			NP_001341168.1
ANK2	NM_001354243.2	c.21+29807C>G		intron_variant			NP_001341172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK2	ENST00000506722.5	c.21+29807C>G		intron_variant		1		ENSP00000421067
ANK2	ENST00000503271.5	c.21+29807C>G		intron_variant		2		ENSP00000423799
ANK2	ENST00000503423.6	c.21+29807C>G		intron_variant		5		ENSP00000421011	A2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18908 AN: 151942 Hom.: 2037 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0946

Gnomad ASJ AF: 0.0857

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0387

Gnomad OTH AF: 0.109

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

GnomAD4 genome AF: 0.125 AC: 18966 AN: 152060 Hom.: 2050 Cov.: 32 AF XY: 0.129 AC XY: 9610 AN XY: 74332

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.0949

Gnomad4 ASJ AF: 0.0857

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.0745

Gnomad4 NFE AF: 0.0387

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0799 Hom.: 114

Bravo AF: 0.128

Asia WGS AF: 0.350 AC: 1214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.35
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12500579; hg19: chr4-113855477; COSMIC: COSV72390483;