10-60196628-GAAA-GAAAAAAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_020987.5(ANK3):c.1690-7_1690-4dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,260,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

ANK3
NM_020987.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 10-60196628-G-GAAAA is Benign according to our data. Variant chr10-60196628-G-GAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3037817.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000293 (39/133118) while in subpopulation AFR AF = 0.000969 (36/37136). AF 95% confidence interval is 0.000719. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

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.1690-7_1690-4dupTTTT	splice_region intron	N/A	NP_066267.2
ANK3	NM_001204404.2		c.1639-7_1639-4dupTTTT	splice_region intron	N/A	NP_001191333.1	Q12955-4
ANK3	NM_001320874.2		c.1690-7_1690-4dupTTTT	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_1690-3insTTTT	splice_region intron	N/A	ENSP00000280772.1	Q12955-3
ANK3	ENST00000373827.6	TSL:1	c.1672-4_1672-3insTTTT	splice_region intron	N/A	ENSP00000362933.2	Q12955-5
ANK3	ENST00000503366.6	TSL:2	c.1639-4_1639-3insTTTT	splice_region intron	N/A	ENSP00000425236.1	Q12955-4

Frequencies

GnomAD3 genomes

AF:

0.000293

AC:

AN:

133084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000971

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000639

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00167

AC:

189

AN:

113098

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.00944

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.000407

Gnomad EAS exome

AF:

0.00583

Gnomad FIN exome

AF:

0.000126

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00106

GnomAD4 exome

AF:

0.000563

AC:

635

AN:

1127110

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

291

AN XY:

565044

show subpopulations

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

African (AFR)

AF:

0.0112

AC:

291

AN:

26030

American (AMR)

AF:

0.000792

AC:

AN:

32808

Ashkenazi Jewish (ASJ)

AF:

0.000238

AC:

AN:

21018

East Asian (EAS)

AF:

0.00439

AC:

147

AN:

33492

South Asian (SAS)

AF:

0.000370

AC:

AN:

67524

European-Finnish (FIN)

AF:

0.000107

AC:

AN:

37376

Middle Eastern (MID)

AF:

0.00128

AC:

AN:

4676

European-Non Finnish (NFE)

AF:

0.000105

AC:

AN:

856940

Other (OTH)

AF:

0.000868

AC:

AN:

47246

⚠️ 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: 0.300

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000293

AC:

AN:

133118

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

63858

show subpopulations

African (AFR)

AF:

0.000969

AC:

AN:

37136

American (AMR)

AF:

0.00

AC:

AN:

13050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3192

East Asian (EAS)

AF:

0.000641

AC:

AN:

4680

South Asian (SAS)

AF:

0.00

AC:

AN:

4208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60988

Other (OTH)

AF:

0.00

AC:

AN:

1790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000295

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ANK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.47

Mutation Taster

=95/5

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over