10-60196628-GAA-GAAAA

Position:

• chr10-60196628-GAA-GAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 210146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1690-5_1690-4dupTT		splice_region_variant, intron_variant		ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.1639-5_1639-4dupTT		splice_region_variant, intron_variant			NP_001191333.1
ANK3	NM_001320874.2	c.1690-5_1690-4dupTT		splice_region_variant, intron_variant			NP_001307803.1
ANK3	NM_001204403.2	c.1672-5_1672-4dupTT		splice_region_variant, intron_variant			NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.1690-5_1690-4dupTT		splice_region_variant, intron_variant		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

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

Gnomad4 AFR exome AF: 0.0540

Gnomad4 AMR exome AF: 0.00607

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.00510

Gnomad4 SAS exome AF: 0.00754

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00426

Gnomad4 OTH exome AF: 0.00804

GnomAD4 genome AF: 0.0130 AC: 1728 AN: 133102 Hom.: 43 Cov.: 28 AF XY: 0.0127 AC XY: 814 AN XY: 63854

Gnomad4 AFR AF: 0.0433

Gnomad4 AMR AF: 0.00514

Gnomad4 ASJ AF: 0.000627

Gnomad4 EAS AF: 0.00150

Gnomad4 SAS AF: 0.00143

Gnomad4 FIN AF: 0.000142

Gnomad4 NFE AF: 0.000246

Gnomad4 OTH AF: 0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 23, 2015

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34796699; hg19: chr10-61956386;