rs117475706

Variant names:

• chr10-60075299-G-A
• rs117475706
• NM_020987.5:c.5582C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3 BP4_Strong BS1 BS2

The NM_020987.5(ANK3):​c.5582C>T​(p.Thr1861Met) variant causes a missense change. The variant allele was found at a frequency of 0.00431 in 1,614,154 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002568426: "Well-established functional studies show damaging effect on the gene or gene product (PS3, see PMID:31451636)."". Synonymous variant affecting the same amino acid position (i.e. T1861T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (17 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 5.50
• Publications: 10 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)

ENSG00000232682 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002568426: "Well-established functional studies show damaging effect on the gene or gene product (PS3, see PMID:31451636)."
• BP4: Computational evidence support a benign effect (MetaRNN=0.006896615).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00285 (434/152346) while in subpopulation NFE AF = 0.00484 (329/68028). AF 95% confidence interval is 0.00441. There are 0 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 Unknown,AR,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.5582C>T	p.Thr1861Met	missense	Exon 37 of 44	NP_066267.2
	ANK3	NM_001204404.2		c.4408+5238C>T		intron	N/A	NP_001191333.1	Q12955-4
	ANK3	NM_001320874.2		c.4405+5238C>T		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.5582C>T	p.Thr1861Met	missense	Exon 37 of 44	ENSP00000280772.1	Q12955-3
	ANK3	ENST00000373827.6	TSL:1	c.4387+5238C>T		intron	N/A	ENSP00000362933.2	Q12955-5
	ANK3	ENST00000355288.6	TSL:1	c.1807+5238C>T		intron	N/A	ENSP00000347436.2	Q12955-6

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00259 AC: 647 AN: 250042 AF XY: 0.00239

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00447 AC: 6529 AN: 1461808 Hom.: 17 Cov.: 35 AF XY: 0.00433 AC XY: 3148 AN XY: 727210

African (AFR) AF: 0.000478 AC: 16 AN: 33474

American (AMR) AF: 0.00145 AC: 65 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00154 AC: 82 AN: 53394

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00545 AC: 6057 AN: 1111972

Other (OTH) AF: 0.00339 AC: 205 AN: 60396

GnomAD4 genome AF: 0.00285 AC: 434 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00264 AC XY: 197 AN XY: 74494

African (AFR) AF: 0.00118 AC: 49 AN: 41590

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00484 AC: 329 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00392 Hom.: 2

Bravo AF: 0.00285

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	-	Intellectual disability-hypotonia-spasticity-sleep disorder syndrome (4)
-	-	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	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.0038
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.080
Sift	Uncertain	0.0030	D
Polyphen		0.11	B
Vest4		0.17
MVP		0.59
MPC		0.36
ClinPred		0.032	T
GERP RS		4.7
Varity_R		0.094
gMVP		0.47
Mutation Taster		=30/70	disease causing

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: rs117475706; hg19: chr10-61835057;