chr10-60196628-G-GAAA

Variant names:

• chr10-60196628-G-GAAA
• rs34796699
• NM_020987.5:c.1690-6_1690-4dupTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020987.5(ANK3):​c.1690-6_1690-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,258,284 control chromosomes in the GnomAD database, including 397 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (335 hom., cov: 28)
  • Exomes 𝑓: 0.0069 (62 hom.)
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: 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-GAAA is Benign according to our data. Variant chr10-60196628-G-GAAA is described in ClinVar as Benign. ClinVar VariationId is 210147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1690-6_1690-4dupTTT		splice_region_variant, intron_variant	Intron 14 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.1639-6_1639-4dupTTT		splice_region_variant, intron_variant	Intron 14 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.1690-6_1690-4dupTTT		splice_region_variant, intron_variant	Intron 14 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.1672-6_1672-4dupTTT		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_1690-3insTTT		splice_region_variant, intron_variant	Intron 14 of 43	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.0446 AC: 5937 AN: 132968 Hom.: 334 Cov.: 28

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00256

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.00595

Gnomad EAS AF: 0.0606

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00313

Gnomad MID AF: 0.0310

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0225 AC: 2550 AN: 113098 AF XY: 0.0190

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.00957

Gnomad EAS exome AF: 0.0675

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.00689 AC: 7750 AN: 1125286 Hom.: 62 Cov.: 21 AF XY: 0.00664 AC XY: 3749 AN XY: 564232

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

African (AFR) AF: 0.111 AC: 2854 AN: 25692

American (AMR) AF: 0.0109 AC: 357 AN: 32746

Ashkenazi Jewish (ASJ) AF: 0.00686 AC: 144 AN: 20978

East Asian (EAS) AF: 0.0633 AC: 2098 AN: 33128

South Asian (SAS) AF: 0.00429 AC: 289 AN: 67400

European-Finnish (FIN) AF: 0.00212 AC: 79 AN: 37314

Middle Eastern (MID) AF: 0.0292 AC: 136 AN: 4660

European-Non Finnish (NFE) AF: 0.00135 AC: 1152 AN: 856220

Other (OTH) AF: 0.0136 AC: 641 AN: 47148

⚠️ 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: 0.0447 AC: 5951 AN: 132998 Hom.: 335 Cov.: 28 AF XY: 0.0444 AC XY: 2832 AN XY: 63800

African (AFR) AF: 0.136 AC: 5033 AN: 37038

American (AMR) AF: 0.0268 AC: 349 AN: 13036

Ashkenazi Jewish (ASJ) AF: 0.00595 AC: 19 AN: 3192

East Asian (EAS) AF: 0.0605 AC: 283 AN: 4674

South Asian (SAS) AF: 0.00499 AC: 21 AN: 4208

European-Finnish (FIN) AF: 0.00313 AC: 22 AN: 7022

Middle Eastern (MID) AF: 0.0336 AC: 9 AN: 268

European-Non Finnish (NFE) AF: 0.00231 AC: 141 AN: 60988

Other (OTH) AF: 0.0402 AC: 72 AN: 1790

Alfa AF: 0.00379 Hom.: 21

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 12, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2017

Genetic Services Laboratory, University of Chicago

Significance: 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 (auto)

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;