10-60196628-GAA-GAAA

Position:

• chr10-60196628-GAA-GAAA

Variant summary

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

The NM_020987.5(ANK3):​c.1690-4_1690-3insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 132,804 control chromosomes in the GnomAD database, including 956 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (956 hom., cov: 28)
  • Exomes 𝑓: 0.26 (692 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANK3 NM_020987.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: 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-GA is Benign according to our data. Variant chr10-60196628-G-GA is described in ClinVar as [Benign]. Clinvar id is 802577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.1690-4_1690-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000280772.7
ANK3	NM_001204403.2	c.1672-4_1672-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ANK3	NM_001204404.2	c.1639-4_1639-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ANK3	NM_001320874.2	c.1690-4_1690-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.1690-4_1690-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.112 AC: 14833 AN: 132772 Hom.: 954 Cov.: 28

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0435

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0897

Gnomad NFE AF: 0.0790

Gnomad OTH AF: 0.101

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.263 AC: 251852 AN: 956172 Hom.: 692 Cov.: 21 AF XY: 0.267 AC XY: 126959 AN XY: 475462

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.282

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.112 AC: 14839 AN: 132804 Hom.: 956 Cov.: 28 AF XY: 0.111 AC XY: 7057 AN XY: 63652

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0842

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0671

Gnomad4 NFE AF: 0.0790

Gnomad4 OTH AF: 0.0997

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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;