rs114937210

Variant names:

• chr10-60278806-T-C
• rs114937210
• NM_020987.5:c.382A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020987.5(ANK3):​c.382A>G​(p.Thr128Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00186 in 1,613,940 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.26
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005452752).
• BP6: Variant 10-60278806-T-C is Benign according to our data. Variant chr10-60278806-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128369.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 = 0.0101 (1539/152264) while in subpopulation AFR AF = 0.0358 (1488/41546). AF 95% confidence interval is 0.0343. There are 43 homozygotes in GnomAd4. There are 735 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.382A>G	p.Thr128Ala	missense	Exon 4 of 44	NP_066267.2
	ANK3	NM_001204404.2		c.331A>G	p.Thr111Ala	missense	Exon 4 of 44	NP_001191333.1	Q12955-4
	ANK3	NM_001320874.2		c.382A>G	p.Thr128Ala	missense	Exon 4 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.382A>G	p.Thr128Ala	missense	Exon 4 of 44	ENSP00000280772.1	Q12955-3
	ANK3	ENST00000373827.6	TSL:1	c.364A>G	p.Thr122Ala	missense	Exon 5 of 44	ENSP00000362933.2	Q12955-5
	ANK3	ENST00000503366.6	TSL:2	c.331A>G	p.Thr111Ala	missense	Exon 4 of 44	ENSP00000425236.1	Q12955-4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1532 AN: 152146 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00262 AC: 657 AN: 251086 AF XY: 0.00170

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00100 AC: 1461 AN: 1461676 Hom.: 28 Cov.: 31 AF XY: 0.000827 AC XY: 601 AN XY: 727146

African (AFR) AF: 0.0354 AC: 1186 AN: 33472

American (AMR) AF: 0.00204 AC: 91 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111850

Other (OTH) AF: 0.00214 AC: 129 AN: 60382

GnomAD4 genome AF: 0.0101 AC: 1539 AN: 152264 Hom.: 43 Cov.: 32 AF XY: 0.00987 AC XY: 735 AN XY: 74438

African (AFR) AF: 0.0358 AC: 1488 AN: 41546

American (AMR) AF: 0.00235 AC: 36 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00354 Hom.: 18

Bravo AF: 0.0116

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00306 AC: 371

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ANK3-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.010
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-1.3	N
PhyloP100		4.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Benign	0.054	T
Sift4G	Benign	0.33	T
Polyphen		0.99	D
Vest4		0.24
MVP		0.60
MPC		1.1
ClinPred		0.021	T
GERP RS		5.4
Varity_R		0.14
gMVP		0.18
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs114937210; hg19: chr10-62038564;