dbSNP rs41283526: ANK3:c.2615-6882A>G (chr10-60145969-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001204404.2(ANK3):c.2616A>G(p.Lys872Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 892,554 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 45 hom. )

Consequence

ANK3
NM_001204404.2 splice_region, synonymous

Scores

Splicing: ADA: 0.01046

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.07

Publications

11 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), Ambry Genetics, Orphanet
intellectual disability
Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen
Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ANK3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001204404.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.2).

BP6

Variant 10-60145969-T-C is Benign according to our data. Variant chr10-60145969-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00795 (1211/152286) while in subpopulation NFE AF = 0.0109 (741/68026). AF 95% confidence interval is 0.0102. There are 10 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 Unknown,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK3	NM_020987.5	MANE Select	c.2615-6882A>G		intron	N/A	NP_066267.2
ANK3	NM_001204404.2		c.2616A>G	p.Lys872Lys	splice_region synonymous	Exon 24 of 44	NP_001191333.1	Q12955-4
ANK3	NM_001320874.2		c.2615-6882A>G		intron	N/A	NP_001307803.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK3	ENST00000280772.7	TSL:1 MANE Select	c.2615-6882A>G		intron	N/A	ENSP00000280772.1	Q12955-3
ANK3	ENST00000373827.6	TSL:1	c.2597-6882A>G		intron	N/A	ENSP00000362933.2	Q12955-5
ANK3	ENST00000503366.6	TSL:2	c.2616A>G	p.Lys872Lys	splice_region synonymous	Exon 24 of 44	ENSP00000425236.1	Q12955-4

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1213

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00762

AC:

1023

AN:

134260

AF XY:

0.00728

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00450

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0188

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00557

GnomAD4 exome

AF:

0.00950

AC:

7036

AN:

740268

Hom.:

Cov.:

AF XY:

0.00906

AC XY:

3525

AN XY:

389108

show subpopulations

African (AFR)

AF:

0.00288

AC:

AN:

19420

American (AMR)

AF:

0.00518

AC:

181

AN:

34912

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

254

AN:

21180

East Asian (EAS)

AF:

0.00

AC:

AN:

32832

South Asian (SAS)

AF:

0.000648

AC:

AN:

66404

European-Finnish (FIN)

AF:

0.0176

AC:

593

AN:

33678

Middle Eastern (MID)

AF:

0.00470

AC:

AN:

4466

European-Non Finnish (NFE)

AF:

0.0114

AC:

5578

AN:

490652

Other (OTH)

AF:

0.00844

AC:

310

AN:

36724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

331

663

994

1326

1657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00795

AC:

1211

AN:

152286

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

602

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41570

American (AMR)

AF:

0.00432

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0224

AC:

238

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

741

AN:

68026

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00984

Hom.:

Bravo

AF:

0.00686

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

ANK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

3.1

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.010

dbscSNV1_RF

Benign

0.032

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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