10-60196628-GAAA-GAAAAA

Variant names:

• chr10-60196628-G-GAA
• rs34796699
• NM_020987.5:c.1690-5_1690-4dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020987.5(ANK3):​c.1690-5_1690-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 1,247,256 control chromosomes in the GnomAD database, including 51 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 28)
  • Exomes 𝑓: 0.0058 (8 hom.)
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.469
• Publications: 5 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 10-60196628-G-GAA is Benign according to our data. Variant chr10-60196628-G-GAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1728/133102) while in subpopulation AFR AF = 0.0433 (1609/37128). AF 95% confidence interval is 0.0416. There are 43 homozygotes in GnomAd4. There are 814 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1690-5_1690-4dupTT		splice_region_variant, intron_variant	Intron 14 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.1639-5_1639-4dupTT		splice_region_variant, intron_variant	Intron 14 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.1690-5_1690-4dupTT		splice_region_variant, intron_variant	Intron 14 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.1672-5_1672-4dupTT		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_1690-3insTT		splice_region_variant, intron_variant	Intron 14 of 43	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1728 AN: 133068 Hom.: 43 Cov.: 28

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00522

Gnomad ASJ AF: 0.000627

Gnomad EAS AF: 0.00149

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000246

Gnomad OTH AF: 0.0118

GnomAD2 exomes AF: 0.0106 AC: 1204 AN: 113098 AF XY: 0.00923

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.00920

Gnomad ASJ exome AF: 0.00509

Gnomad EAS exome AF: 0.00934

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00601

GnomAD4 exome AF: 0.00576 AC: 6415 AN: 1114154 Hom.: 8 Cov.: 21 AF XY: 0.00577 AC XY: 3225 AN XY: 558592

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

African (AFR) AF: 0.0540 AC: 1391 AN: 25782

American (AMR) AF: 0.00607 AC: 197 AN: 32434

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 63 AN: 20798

East Asian (EAS) AF: 0.00510 AC: 169 AN: 33158

South Asian (SAS) AF: 0.00754 AC: 501 AN: 66432

European-Finnish (FIN) AF: 0.00217 AC: 80 AN: 36938

Middle Eastern (MID) AF: 0.00691 AC: 32 AN: 4630

European-Non Finnish (NFE) AF: 0.00426 AC: 3607 AN: 847342

Other (OTH) AF: 0.00804 AC: 375 AN: 46640

⚠️ 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 AF: 0.0130 AC: 1728 AN: 133102 Hom.: 43 Cov.: 28 AF XY: 0.0127 AC XY: 814 AN XY: 63854

African (AFR) AF: 0.0433 AC: 1609 AN: 37128

American (AMR) AF: 0.00514 AC: 67 AN: 13046

Ashkenazi Jewish (ASJ) AF: 0.000627 AC: 2 AN: 3192

East Asian (EAS) AF: 0.00150 AC: 7 AN: 4680

South Asian (SAS) AF: 0.00143 AC: 6 AN: 4208

European-Finnish (FIN) AF: 0.000142 AC: 1 AN: 7022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000246 AC: 15 AN: 60986

Other (OTH) AF: 0.0117 AC: 21 AN: 1790

Alfa AF: 0.00497 Hom.: 21

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=99/1	polymorphism

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;