Genetic Variant ANK3:c.114+49629G>A (chr10-60339796-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020987.5(ANK3):c.114+49629G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,956 control chromosomes in the GnomAD database, including 19,694 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 0.50 ( 19694 hom., cov: 33)

Consequence

ANK3
NM_020987.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.79

Publications

4 publications found

Variant links:

Genes affected

ANK3 (HGNC:494): (ankyrin 3) Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. 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. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ANK3 Gene-Disease associations (from GenCC):

intellectual disability-hypotonia-spasticity-sleep disorder syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
intellectual disability
Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ANK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5 link	c.114+49629G>A	intron_variant	Intron 1 of 43	ENST00000280772.7	NP_066267.2	Q12955-3
ANK3	NM_001204404.2 link	c.64-60157G>A	intron_variant	Intron 1 of 43		NP_001191333.1	Q12955-4
ANK3	NM_001320874.2 link	c.114+49629G>A	intron_variant	Intron 1 of 42		NP_001307803.1
ANK3	NM_001204403.2 link	c.97-60157G>A	intron_variant	Intron 2 of 43		NP_001191332.1	Q12955-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 link	c.114+49629G>A		intron_variant	Intron 1 of 43	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

AF:

0.502

AC:

76223

AN:

151838

Hom.:

19679

Cov.:

show subpopulations

Gnomad AFR

AF:

0.395

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.552

Gnomad ASJ

AF:

0.520

Gnomad EAS

AF:

0.690

Gnomad SAS

AF:

0.605

Gnomad FIN

AF:

0.606

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.519

Gnomad OTH

AF:

0.505

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

GnomAD4 genome

AF:

0.502

AC:

76277

AN:

151956

Hom.:

19694

Cov.:

AF XY:

0.512

AC XY:

38021

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.395

AC:

16366

AN:

41434

American (AMR)

AF:

0.553

AC:

8437

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.520

AC:

1805

AN:

3470

East Asian (EAS)

AF:

0.689

AC:

3560

AN:

5170

South Asian (SAS)

AF:

0.603

AC:

2904

AN:

4816

European-Finnish (FIN)

AF:

0.606

AC:

6382

AN:

10536

Middle Eastern (MID)

AF:

0.589

AC:

172

AN:

292

European-Non Finnish (NFE)

AF:

0.519

AC:

35254

AN:

67966

Other (OTH)

AF:

0.507

AC:

1068

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1931

3862

5794

7725

9656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.508

Hom.:

5003

Bravo

AF:

0.490

Asia WGS

AF:

0.624

AC:

2169

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.077

(source)

DANN

Benign

0.70

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over