10-60196628-GAAA-GAAAAAAAAA

Variant names:

• chr10-60196628-G-GAAAAAA
• rs34796699
• NM_020987.5:c.1690-9_1690-4dupTTTTTT

Variant summary

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

The NM_020987.5(ANK3):​c.1690-9_1690-4dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000266 in 1,127,612 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: 𝑓 0.0 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469
• Publications: 0 publications found

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)

ACMG classification

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1690-9_1690-4dupTTTTTT		splice_region_variant, intron_variant	Intron 14 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.1639-9_1639-4dupTTTTTT		splice_region_variant, intron_variant	Intron 14 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.1690-9_1690-4dupTTTTTT		splice_region_variant, intron_variant	Intron 14 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.1672-9_1672-4dupTTTTTT		splice_region_variant, intron_variant	Intron 15 of 43		NP_001191332.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 133090 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000266 AC: 3 AN: 1127612 Hom.: 0 Cov.: 21 AF XY: 0.00000177 AC XY: 1 AN XY: 565328

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

African (AFR) AF: 0.000115 AC: 3 AN: 26170

American (AMR) AF: 0.00 AC: 0 AN: 32842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21026

East Asian (EAS) AF: 0.00 AC: 0 AN: 33606

South Asian (SAS) AF: 0.00 AC: 0 AN: 67568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 857054

Other (OTH) AF: 0.00 AC: 0 AN: 47286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 133090 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 63810

African (AFR) AF: 0.00 AC: 0 AN: 37066

American (AMR) AF: 0.00 AC: 0 AN: 13036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3192

East Asian (EAS) AF: 0.00 AC: 0 AN: 4696

South Asian (SAS) AF: 0.00 AC: 0 AN: 4232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60998

Other (OTH) AF: 0.00 AC: 0 AN: 1774

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

Other links and lift over

dbSNP: rs34796699; hg19: chr10-61956386;