10-60196628-GAAA-GAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_020987.5(ANK3):c.1690-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 132,804 control chromosomes in the GnomAD database, including 956 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 956 hom., cov: 28)

Exomes 𝑓: 0.26 ( 692 hom. )

Failed GnomAD Quality Control

Consequence

ANK3
NM_020987.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.469

Publications

5 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: Orphanet, Labcorp Genetics (formerly Invitae), 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 -16 ACMG points.

BP6

Variant 10-60196628-G-GA is Benign according to our data. Variant chr10-60196628-G-GA is described in ClinVar as Benign. ClinVar VariationId is 802577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020987.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANK3	NM_020987.5	MANE Select	c.1690-4dupT	splice_region intron	N/A	NP_066267.2
ANK3	NM_001204404.2		c.1639-4dupT	splice_region intron	N/A	NP_001191333.1	Q12955-4
ANK3	NM_001320874.2		c.1690-4dupT	splice_region intron	N/A	NP_001307803.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANK3	ENST00000280772.7	TSL:1 MANE Select	c.1690-4_1690-3insT	splice_region intron	N/A	ENSP00000280772.1	Q12955-3
ANK3	ENST00000373827.6	TSL:1	c.1672-4_1672-3insT	splice_region intron	N/A	ENSP00000362933.2	Q12955-5
ANK3	ENST00000503366.6	TSL:2	c.1639-4_1639-3insT	splice_region intron	N/A	ENSP00000425236.1	Q12955-4

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

14833

AN:

132772

Hom.:

954

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.0435

Gnomad AMR

AF:

0.0843

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.0671

Gnomad MID

AF:

0.0897

Gnomad NFE

AF:

0.0790

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.313

AC:

35412

AN:

113098

AF XY:

0.318

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.350

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.313

Gnomad FIN exome

AF:

0.263

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.263

AC:

251852

AN:

956172

Hom.:

692

Cov.:

AF XY:

0.267

AC XY:

126959

AN XY:

475462

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.262

AC:

6266

AN:

23934

American (AMR)

AF:

0.270

AC:

6996

AN:

25886

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

4575

AN:

16310

East Asian (EAS)

AF:

0.282

AC:

7361

AN:

26088

South Asian (SAS)

AF:

0.318

AC:

17078

AN:

53750

European-Finnish (FIN)

AF:

0.261

AC:

7447

AN:

28488

Middle Eastern (MID)

AF:

0.189

AC:

778

AN:

4114

European-Non Finnish (NFE)

AF:

0.258

AC:

190677

AN:

738362

Other (OTH)

AF:

0.272

AC:

10674

AN:

39240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.345

Heterozygous variant carriers

15797

31594

47390

63187

78984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6962

13924

20886

27848

34810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.112

AC:

14839

AN:

132804

Hom.:

956

Cov.:

AF XY:

0.111

AC XY:

7057

AN XY:

63652

show subpopulations

African (AFR)

AF:

0.188

AC:

6986

AN:

37094

American (AMR)

AF:

0.0842

AC:

1097

AN:

13028

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

248

AN:

3186

East Asian (EAS)

AF:

0.101

AC:

471

AN:

4668

South Asian (SAS)

AF:

0.126

AC:

527

AN:

4198

European-Finnish (FIN)

AF:

0.0671

AC:

469

AN:

6994

Middle Eastern (MID)

AF:

0.0933

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.0790

AC:

4804

AN:

60800

Other (OTH)

AF:

0.0997

AC:

178

AN:

1786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

598

1196

1795

2393

2991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.118

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.47

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over