rs11815168

Positions:

• chr10-60072373-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020987.5(ANK3):​c.8508T>C​(p.His2836=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0061 in 1,613,978 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (42 hom.)
• Consequence: ANK3 NM_020987.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0550

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 10-60072373-A-G is Benign according to our data. Variant chr10-60072373-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.055 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00425 (648/152294) while in subpopulation NFE AF= 0.00672 (457/68028). AF 95% confidence interval is 0.00621. There are 6 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 32. 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	UniProt
ANK3	NM_020987.5	c.8508T>C	p.His2836=	synonymous_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.8508T>C	p.His2836=	synonymous_variant	37/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 152176 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00672

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00423 AC: 1061 AN: 250542 Hom.: 3 AF XY: 0.00461 AC XY: 624 AN XY: 135370

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00520

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.00645

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00629 AC: 9198 AN: 1461684 Hom.: 42 Cov.: 36 AF XY: 0.00620 AC XY: 4510 AN XY: 727150

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00390

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00587

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00718

Gnomad4 OTH exome AF: 0.00609

GnomAD4 genome AF: 0.00425 AC: 648 AN: 152294 Hom.: 6 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74462

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00672

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00499 Hom.: 1

Bravo AF: 0.00424

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00693

EpiControl AF: 0.00664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ANK3: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.5
DANN	Benign	0.56

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: rs11815168; hg19: chr10-61832131;