10-60196628-GAA-GAAAAAA

Position:

• chr10-60196628-GAA-GAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_020987.5(ANK3):​c.1690-7_1690-4dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,260,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-60196628-G-GAAAA is Benign according to our data. Variant chr10-60196628-G-GAAAA is described in ClinVar as [Likely_benign]. Clinvar id is 3037817.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000563 (635/1127110) while in subpopulation AFR AF= 0.0112 (291/26030). AF 95% confidence interval is 0.0101. There are 0 homozygotes in gnomad4_exome. There are 291 alleles in male gnomad4_exome subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1690-7_1690-4dupTTTT		splice_region_variant, intron_variant		ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.1639-7_1639-4dupTTTT		splice_region_variant, intron_variant			NP_001191333.1
ANK3	NM_001320874.2	c.1690-7_1690-4dupTTTT		splice_region_variant, intron_variant			NP_001307803.1
ANK3	NM_001204403.2	c.1672-7_1672-4dupTTTT		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.1690-7_1690-4dupTTTT		splice_region_variant, intron_variant		1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.000293 AC: 39 AN: 133084 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000639

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000563 AC: 635 AN: 1127110 Hom.: 0 Cov.: 21 AF XY: 0.000515 AC XY: 291 AN XY: 565044

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000792

Gnomad4 ASJ exome AF: 0.000238

Gnomad4 EAS exome AF: 0.00439

Gnomad4 SAS exome AF: 0.000370

Gnomad4 FIN exome AF: 0.000107

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000868

GnomAD4 genome AF: 0.000293 AC: 39 AN: 133118 Hom.: 0 Cov.: 28 AF XY: 0.000235 AC XY: 15 AN XY: 63858

Gnomad4 AFR AF: 0.000969

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000641

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ANK3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;