Genetic Variant ANK3:p.Gly1362Glu (chr10-60083607-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020987.5(ANK3):c.4085G>A(p.Gly1362Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1362A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

ANK3
NM_020987.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

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:

ENSG00000232682 (HGNC:):

ENSG00000232682 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

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	UniProt
ANK3	NM_020987.5	MANE Select	c.4085G>A	p.Gly1362Glu	missense	Exon 33 of 44	NP_066267.2
ANK3	NM_001204404.2		c.4088G>A	p.Gly1363Glu	missense	Exon 34 of 44	NP_001191333.1	Q12955-4
ANK3	NM_001320874.2		c.4085G>A	p.Gly1362Glu	missense	Exon 33 of 43	NP_001307803.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANK3	ENST00000280772.7	TSL:1 MANE Select	c.4085G>A	p.Gly1362Glu	missense	Exon 33 of 44	ENSP00000280772.1	Q12955-3
ANK3	ENST00000373827.6	TSL:1	c.4067G>A	p.Gly1356Glu	missense	Exon 34 of 44	ENSP00000362933.2	Q12955-5
ANK3	ENST00000355288.6	TSL:1	c.1487G>A	p.Gly496Glu	missense	Exon 11 of 21	ENSP00000347436.2	Q12955-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-8.0

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.79

MutPred

0.46

Gain of solvent accessibility (P = 0.012)

MVP

0.48

MPC

0.71

ClinPred

1.0

GERP RS

5.8

Varity_R

0.76

gMVP

0.48

Mutation Taster

=26/74

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over