rs28932171

Variant names:

• chr10-60071532-T-C
• rs28932171
• NM_020987.5:c.9349A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020987.5(ANK3):​c.9349A>G​(p.Ile3117Val) variant causes a missense change. The variant allele was found at a frequency of 0.0925 in 1,611,226 control chromosomes in the GnomAD database, including 7,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (540 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7375 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.21
• Publications: 18 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: Labcorp Genetics (formerly Invitae), Orphanet, 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)

ENSG00000232682 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015985668).
• BP6: Variant 10-60071532-T-C is Benign according to our data. Variant chr10-60071532-T-C is described in ClinVar as Benign. ClinVar VariationId is 128384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

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.9349A>G	p.Ile3117Val	missense	Exon 37 of 44	NP_066267.2
	ANK3	NM_001204404.2		c.4409-3523A>G		intron	N/A	NP_001191333.1
	ANK3	NM_001320874.2		c.4406-3523A>G		intron	N/A	NP_001307803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.9349A>G	p.Ile3117Val	missense	Exon 37 of 44	ENSP00000280772.1
	ANK3	ENST00000373827.6	TSL:1	c.4388-3523A>G		intron	N/A	ENSP00000362933.2
	ANK3	ENST00000355288.6	TSL:1	c.1808-3523A>G		intron	N/A	ENSP00000347436.2

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10895 AN: 152032 Hom.: 540 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.0574

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0761

GnomAD2 exomes AF: 0.0720 AC: 18059 AN: 250954 AF XY: 0.0724

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0499

Gnomad ASJ exome AF: 0.0611

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0955

GnomAD4 exome AF: 0.0946 AC: 138095 AN: 1459076 Hom.: 7375 Cov.: 41 AF XY: 0.0929 AC XY: 67421 AN XY: 725810

African (AFR) AF: 0.0150 AC: 503 AN: 33470

American (AMR) AF: 0.0533 AC: 2381 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1640 AN: 26096

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39698

South Asian (SAS) AF: 0.0214 AC: 1848 AN: 86156

European-Finnish (FIN) AF: 0.0857 AC: 4570 AN: 53298

Middle Eastern (MID) AF: 0.0793 AC: 457 AN: 5762

European-Non Finnish (NFE) AF: 0.109 AC: 121498 AN: 1109646

Other (OTH) AF: 0.0861 AC: 5191 AN: 60284

GnomAD4 genome AF: 0.0716 AC: 10889 AN: 152150 Hom.: 540 Cov.: 32 AF XY: 0.0668 AC XY: 4972 AN XY: 74382

African (AFR) AF: 0.0199 AC: 826 AN: 41528

American (AMR) AF: 0.0698 AC: 1067 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 199 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4814

European-Finnish (FIN) AF: 0.0774 AC: 819 AN: 10588

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7647 AN: 67976

Other (OTH) AF: 0.0754 AC: 159 AN: 2110

Alfa AF: 0.0859 Hom.: 466

Bravo AF: 0.0687

TwinsUK AF: 0.108 AC: 400

ALSPAC AF: 0.0986 AC: 380

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.110 AC: 942

ExAC AF: 0.0744 AC: 9027

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ANK3-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.090
Sift	Benign	0.31	T
Polyphen		0.0090	B
Vest4		0.099
MPC		0.12
ClinPred		0.010	T
GERP RS		5.2
Varity_R		0.079
gMVP		0.098
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28932171; hg19: chr10-61831290; COSMIC: COSV55062301; COSMIC: COSV55062301;