Genetic Variant ANK2:c.-40+9357C>T (chr4-112827621-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001386142.1(ANK2):c.-40+9357C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 845,392 control chromosomes in the GnomAD database, including 37,248 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 0.30 ( 6917 hom., cov: 32)

Exomes 𝑓: 0.29 ( 30331 hom. )

Consequence

ANK2
NM_001386142.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.378

Variant links:

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 links:

LOC100422627 (HGNC:):

LOC100422627 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
ANK2	NM_001386142.1 link	c.-40+9357C>T	intron_variant	Intron 1 of 44	NP_001373071.1
ANK2	NM_001386143.1 link	c.-40+9357C>T	intron_variant	Intron 1 of 47	NP_001373072.1
ANK2	NM_001386186.2 link	c.72+121404C>T	intron_variant	Intron 1 of 46	NP_001373115.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
ANK2	ENST00000506722.5 link	c.-40+9357C>T	intron_variant	Intron 1 of 46	1	ENSP00000421067.1	Q01484-5
ANK2	ENST00000672209.1 link	c.-40+9357C>T	intron_variant	Intron 1 of 47		ENSP00000499982.1	A0A5F9ZH30
ANK2	ENST00000673298.1 link	c.-40+9357C>T	intron_variant	Intron 1 of 46		ENSP00000500245.1	A0A5F9ZHE4

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45406

AN:

151940

Hom.:

6900

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.338

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.328

GnomAD4 exome

AF:

0.292

AC:

202274

AN:

693334

Hom.:

30331

Cov.:

AF XY:

0.294

AC XY:

108480

AN XY:

368670

show subpopulations

Gnomad4 AFR exome

AF:

0.270

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.332

Gnomad4 SAS exome

AF:

0.325

Gnomad4 FIN exome

AF:

0.338

Gnomad4 NFE exome

AF:

0.274

Gnomad4 OTH exome

AF:

0.311

GnomAD4 genome

AF:

0.299

AC:

45462

AN:

152058

Hom.:

6917

Cov.:

AF XY:

0.301

AC XY:

22377

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.332

Gnomad4 ASJ

AF:

0.307

Gnomad4 EAS

AF:

0.348

Gnomad4 SAS

AF:

0.328

Gnomad4 FIN

AF:

0.338

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.333

Alfa

AF:

0.291

Hom.:

1049

Bravo

AF:

0.300

Asia WGS

AF:

0.389

AC:

1351

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.1

DANN

Benign

0.49

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over