10-60196628-GAA-GA

Position:

• chr10-60196628-GAA-GA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020987.5(ANK3):​c.1690-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,225,208 control chromosomes in the GnomAD database, including 37 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 28)
  • Exomes 𝑓: 0.020 (26 hom.)
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• 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 -10 ACMG points.

• BP6: Variant 10-60196628-GA-G is Benign according to our data. Variant chr10-60196628-GA-G is described in ClinVar as [Benign]. Clinvar id is 1174830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-60196628-GA-G is described in Lovd as [Benign]. Variant chr10-60196628-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1370/133074) while in subpopulation SAS AF= 0.0166 (70/4206). AF 95% confidence interval is 0.0135. There are 11 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1368 AN: 133040 Hom.: 11 Cov.: 28

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00698

Gnomad ASJ AF: 0.0526

Gnomad EAS AF: 0.00767

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.00612

Gnomad OTH AF: 0.0107

GnomAD4 exome AF: 0.0200 AC: 21819 AN: 1092134 Hom.: 26 Cov.: 21 AF XY: 0.0204 AC XY: 11153 AN XY: 547070

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0633

Gnomad4 EAS exome AF: 0.0128

Gnomad4 SAS exome AF: 0.0317

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0232

GnomAD4 genome AF: 0.0103 AC: 1370 AN: 133074 Hom.: 11 Cov.: 28 AF XY: 0.0116 AC XY: 740 AN XY: 63838

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00698

Gnomad4 ASJ AF: 0.0526

Gnomad4 EAS AF: 0.00769

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.00612

Gnomad4 OTH AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;