4-113049760-A-T

Variant names:

• chr4-113049760-A-T
• NM_001148.6:c.32A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001148.6(ANK2):​c.32A>T​(p.Asp11Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANK2 NM_001148.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73
• Publications: 0 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-AS1 (HGNC:40076): (ANK2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.32A>T	p.Asp11Val	missense	Exon 1 of 46	NP_001139.3
	ANK2	NM_001354225.2		c.32A>T	p.Asp11Val	missense	Exon 1 of 47	NP_001341154.1
	ANK2	NM_001354228.2		c.32A>T	p.Asp11Val	missense	Exon 1 of 46	NP_001341157.1	A0A5F9ZH70

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK2	ENST00000357077.9	TSL:1 MANE Select	c.32A>T	p.Asp11Val	missense	Exon 1 of 46	ENSP00000349588.4	Q01484-4
	ANK2	ENST00000394537.7	TSL:1	c.32A>T	p.Asp11Val	missense	Exon 1 of 45	ENSP00000378044.3	Q01484-2
	ANK2	ENST00000506722.5	TSL:1	c.22-124656A>T		intron	N/A	ENSP00000421067.1	Q01484-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.098	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.24		Gain of glycosylation at S12 (P = 0.0036)
MVP		0.72
MPC		1.3
ClinPred		0.97	D
GERP RS		5.3
PromoterAI		-0.031	Neutral
Varity_R		0.42
gMVP		0.68
Mutation Taster		=83/17	polymorphism

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

hg19: chr4-113970916;