rs149682716

Variant names:

• chr10-60114284-G-A
• rs149682716
• NM_020987.5:c.2889C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020987.5(ANK3):​c.2889C>T​(p.Tyr963Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,609,334 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: ANK3 NM_020987.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.306
• Publications: 1 publications found

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]

ANK3 Gene-Disease associations (from GenCC):

• intellectual disability-hypotonia-spasticity-sleep disorder syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• intellectual disability

  Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-60114284-G-A is Benign according to our data. Variant chr10-60114284-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.306 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00274 (418/152336) while in subpopulation AFR AF = 0.00964 (401/41576). AF 95% confidence interval is 0.00887. There are 2 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020987.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	NM_020987.5	MANE Select	c.2889C>T	p.Tyr963Tyr	synonymous	Exon 26 of 44	NP_066267.2
	ANK3	NM_001204404.2		c.2892C>T	p.Tyr964Tyr	synonymous	Exon 27 of 44	NP_001191333.1	Q12955-4
	ANK3	NM_001320874.2		c.2889C>T	p.Tyr963Tyr	synonymous	Exon 26 of 43	NP_001307803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.2889C>T	p.Tyr963Tyr	synonymous	Exon 26 of 44	ENSP00000280772.1	Q12955-3
	ANK3	ENST00000373827.6	TSL:1	c.2871C>T	p.Tyr957Tyr	synonymous	Exon 27 of 44	ENSP00000362933.2	Q12955-5
	ANK3	ENST00000355288.6	TSL:1	c.291C>T	p.Tyr97Tyr	synonymous	Exon 4 of 21	ENSP00000347436.2	Q12955-6

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000777 AC: 192 AN: 247068 AF XY: 0.000516

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000305 AC: 444 AN: 1456998 Hom.: 1 Cov.: 28 AF XY: 0.000270 AC XY: 196 AN XY: 724874

African (AFR) AF: 0.0100 AC: 334 AN: 33242

American (AMR) AF: 0.000456 AC: 20 AN: 43830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1109952

Other (OTH) AF: 0.000665 AC: 40 AN: 60180

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152336 Hom.: 2 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74500

African (AFR) AF: 0.00964 AC: 401 AN: 41576

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00355

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.2
DANN	Benign	0.47
PhyloP100		0.31
PromoterAI		-0.042	Neutral
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs149682716; hg19: chr10-61874042;