rs41274676

chr10-60076416-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_020987.5(ANK3):c.4465C>T(p.Pro1489Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,612,038 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: ANK3 NM_020987.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 9.60

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANK3
• BP4: Computational evidence support a benign effect (MetaRNN=0.042598426).
• BP6: Variant 10-60076416-G-A is Benign according to our data. Variant chr10-60076416-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210161.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANK3	NM_020987.5	c.4465C>T	p.Pro1489Ser	missense_variant	37/44	ENST00000280772.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANK3	ENST00000280772.7	c.4465C>T	p.Pro1489Ser	missense_variant	37/44	1	NM_020987.5

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00172 AC: 427 AN: 248892 Hom.: 2 AF XY: 0.00167 AC XY: 224 AN XY: 134526

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00143

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00249 AC: 3633 AN: 1459828 Hom.: 7 Cov.: 34 AF XY: 0.00242 AC XY: 1759 AN XY: 725968

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000427

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.00223

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74412

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00131

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00303

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	This variant is associated with the following publications: (PMID: 30919572) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ANK3: BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 06, 2015

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ANK3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.043	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.73
MPC		0.28
ClinPred		0.10	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs41274676; hg19: chr10-61836174; COSMIC: COSV55047760; COSMIC: COSV55047760;