10-60042695-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_020987.5(ANK3):​c.13130C>T​(p.Ser4377Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.06
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16623569).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000527 (77/1461726) while in subpopulation NFE AF= 0.0000675 (75/1111922). AF 95% confidence interval is 0.0000551. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANK3NM_020987.5 linkc.13130C>T p.Ser4377Leu missense_variant Exon 43 of 44 ENST00000280772.7 NP_066267.2 Q12955-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANK3ENST00000280772.7 linkc.13130C>T p.Ser4377Leu missense_variant Exon 43 of 44 1 NM_020987.5 ENSP00000280772.1 Q12955-3

Frequencies

GnomAD3 genomes
AF:
0.0000461
AC:
7
AN:
151940
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000115
AC:
29
AN:
251392
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000246
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461726
Hom.:
0
Cov.:
30
AF XY:
0.0000523
AC XY:
38
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000675
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000461
AC:
7
AN:
151940
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000224
Hom.:
0
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000327
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Uncertain:2
Nov 07, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

May 16, 2022
MGZ Medical Genetics Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Nov 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 4377 of the ANK3 protein (p.Ser4377Leu). This variant is present in population databases (rs201169886, gnomAD 0.02%). 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: 930643). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;.;.;.;.;.
Eigen
Benign
-0.053
Eigen_PC
Benign
0.090
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.17
T;T;T;T;T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
0.69
N;.;.;.;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.1
N;N;N;D;N;N
REVEL
Benign
0.14
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;D;D
Polyphen
0.34
B;.;.;.;.;.
Vest4
0.51
MVP
0.30
MPC
0.54
ClinPred
0.25
T
GERP RS
4.7
Varity_R
0.15
gMVP
0.029

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201169886; hg19: chr10-61802453; API