10-60166650-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_020987.5(ANK3):c.2555G>A(p.Arg852His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,510 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.13

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK3
• BP4: Computational evidence support a benign effect (MetaRNN=0.023770362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.2555G>A	p.Arg852His	missense_variant	23/44	ENST00000280772.7
ANK3	NM_001204404.2	c.2504G>A	p.Arg835His	missense_variant	23/44
ANK3	NM_001320874.2	c.2555G>A	p.Arg852His	missense_variant	23/43
ANK3	NM_001204403.2	c.2537G>A	p.Arg846His	missense_variant	24/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.2555G>A	p.Arg852His	missense_variant	23/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 250860 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1461250 Hom.: 2 Cov.: 30 AF XY: 0.000171 AC XY: 124 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000873

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74456

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2016	A variant of uncertain significance has been identified in the ANK3 gene. The R852H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R852H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the R852H variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces arginine with histidine at codon 852 of the ANK3 protein (p.Arg852His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs190358169, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ANK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 252732). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 16, 2015

- -

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Benign	0.81
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.19	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.53	T;T;T;T
Polyphen		0.0040	B;.;.;.
Vest4		0.23
MVP		0.52
MPC		1.5
ClinPred		0.057	T
GERP RS		4.7
Varity_R		0.065
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs190358169; hg19: chr10-61926408; COSMIC: COSV99782204;