Genetic Variant ANK3:c.1690-10_1690-4dupTTTTTTT (chr10-60196628-G-GAAAAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020987.5(ANK3):c.1690-10_1690-4dupTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000887 in 1,127,614 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Consequence

ANK3
NM_020987.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.469

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5 link	c.1690-10_1690-4dupTTTTTTT	splice_region_variant, intron_variant	Intron 14 of 43	ENST00000280772.7	NP_066267.2	Q12955-3
ANK3	NM_001204404.2 link	c.1639-10_1639-4dupTTTTTTT	splice_region_variant, intron_variant	Intron 14 of 43		NP_001191333.1	Q12955-4
ANK3	NM_001320874.2 link	c.1690-10_1690-4dupTTTTTTT	splice_region_variant, intron_variant	Intron 14 of 42		NP_001307803.1
ANK3	NM_001204403.2 link	c.1672-10_1672-4dupTTTTTTT	splice_region_variant, intron_variant	Intron 15 of 43		NP_001191332.1	Q12955-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7 link	c.1690-4_1690-3insTTTTTTT		splice_region_variant, intron_variant	Intron 14 of 43	1	NM_020987.5	ENSP00000280772.1		Q12955-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.87e-7

AC:

AN:

1127614

Hom.:

Cov.:

AF XY:

0.00000177

AC XY:

AN XY:

565328

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26172

American (AMR)

AF:

0.00

AC:

AN:

32842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21026

East Asian (EAS)

AF:

0.00

AC:

AN:

33608

South Asian (SAS)

AF:

0.00

AC:

AN:

67568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

857052

Other (OTH)

AF:

0.00

AC:

AN:

47286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.47

Splicing

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

Publications

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10-60196628-GAAA-GAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over