rs370950407

Positions:

• chr10-60166584-CA-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020987.5(ANK3):​c.2614+6del variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000717 in 1,611,882 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (7 hom.)
• Consequence: ANK3 NM_020987.5 splice_donor_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.30

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 10-60166584-CA-C is Benign according to our data. Variant chr10-60166584-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 128367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00411 (626/152208) while in subpopulation AFR AF= 0.0144 (599/41526). AF 95% confidence interval is 0.0135. There are 6 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5	c.2614+6del		splice_donor_region_variant, intron_variant		ENST00000280772.7	NP_066267.2
ANK3	NM_001204403.2	c.2596+6del		splice_donor_region_variant, intron_variant			NP_001191332.1
ANK3	NM_001204404.2	c.2563+6del		splice_donor_region_variant, intron_variant			NP_001191333.1
ANK3	NM_001320874.2	c.2614+6del		splice_donor_region_variant, intron_variant			NP_001307803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.2614+6del		splice_donor_region_variant, intron_variant		1	NM_020987.5	ENSP00000280772

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152092 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000969 AC: 242 AN: 249858 Hom.: 0 AF XY: 0.000703 AC XY: 95 AN XY: 135048

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000363 AC: 530 AN: 1459674 Hom.: 7 Cov.: 30 AF XY: 0.000313 AC XY: 227 AN XY: 726196

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.000606

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152208 Hom.: 6 Cov.: 33 AF XY: 0.00363 AC XY: 270 AN XY: 74428

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00453

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ANK3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs370950407; hg19: chr10-61926342;