10-60196628-GAA-GAAAAA

Position:

• chr10-60196628-GAA-GAAAAA

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_1690-3insTTT 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 0.0109 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, 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-GAAA is Benign according to our data. Variant chr10-60196628-G-GAAA is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
ANK3	NM_020987.5	c.1690-4_1690-3insTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000280772.7
ANK3	NM_001204403.2	c.1672-4_1672-3insTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ANK3	NM_001204404.2	c.1639-4_1639-3insTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ANK3	NM_001320874.2	c.1690-4_1690-3insTTT		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_1690-3insTTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020987.5

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

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

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.00686

Gnomad4 EAS exome AF: 0.0633

Gnomad4 SAS exome AF: 0.00429

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0447 AC: 5951 AN: 132998 Hom.: 335 Cov.: 28 AF XY: 0.0444 AC XY: 2832 AN XY: 63800

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.00595

Gnomad4 EAS AF: 0.0605

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.00313

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.0402

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2017	- -

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;