chr10-60055697-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_020987.5(ANK3):c.13026C>A(p.Ser4342Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.52

Publications

3 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:

ENSG00000232682 (HGNC:):

ENSG00000232682 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01692298).

BP6

Variant 10-60055697-G-T is Benign according to our data. Variant chr10-60055697-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210145.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00042 (64/152270) while in subpopulation AFR AF = 0.00144 (60/41556). AF 95% confidence interval is 0.00115. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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	HGVSp	Effect	Exon Rank	Protein
ANK3	NM_020987.5	MANE Select	c.13026C>A	p.Ser4342Arg	missense	Exon 42 of 44	NP_066267.2
ANK3	NM_001204404.2		c.5499C>A	p.Ser1833Arg	missense	Exon 42 of 44	NP_001191333.1
ANK3	NM_001320874.2		c.5496C>A	p.Ser1832Arg	missense	Exon 41 of 43	NP_001307803.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANK3	ENST00000280772.7	TSL:1 MANE Select	c.13026C>A	p.Ser4342Arg	missense	Exon 42 of 44	ENSP00000280772.1
ANK3	ENST00000373827.6	TSL:1	c.5478C>A	p.Ser1826Arg	missense	Exon 42 of 44	ENSP00000362933.2
ANK3	ENST00000355288.6	TSL:1	c.2898C>A	p.Ser966Arg	missense	Exon 19 of 21	ENSP00000347436.2

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000112

AC:

AN:

251114

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33456

American (AMR)

AF:

0.000157

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111950

Other (OTH)

AF:

0.000132

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000420

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41556

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000247

Hom.:

Bravo

AF:

0.000672

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 09, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 4342 of the ANK3 protein (p.Ser4342Arg). This variant is present in population databases (rs148498212, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ANK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 210145). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases

Benign:1

Jun 22, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

M_CAP

Benign

0.029

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

1.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.67

REVEL

Benign

0.040

Sift

Uncertain

0.0030

Sift4G

Benign

0.46

Polyphen

0.0010

Vest4

0.22

MutPred

0.28

Loss of phosphorylation at S4342 (P = 0.0013)

MVP

0.37

MPC

0.16

ClinPred

0.054

GERP RS

3.2

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.10

gMVP

0.081

Mutation Taster

=88/12

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over