12-98829332-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001352186.2(ANKS1B):​c.2908C>T​(p.Pro970Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,792 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

ANKS1B
NM_001352186.2 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.52
Variant links:
Genes affected
ANKS1B (HGNC:24600): (ankyrin repeat and sterile alpha motif domain containing 1B) This gene encodes a multi-domain protein that is predominantly expressed in brain and testis. This protein interacts with amyloid beta protein precursor (AbetaPP) and may have a role in normal brain development, and in the pathogenesis of Alzheimer's disease. Expression of this gene has been shown to be elevated in patients with pre-B cell acute lymphocytic leukemia associated with t(1;19) translocation. Alternatively spliced transcript variants encoding different isoforms (some with different subcellular localization, PMID:15004329) have been described for this gene. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANKS1B. . Gene score misZ 2.9457 (greater than the threshold 3.09). Trascript score misZ 3.7643 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
BP4
Computational evidence support a benign effect (MetaRNN=0.25514776).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ANKS1BNM_001352186.2 linkuse as main transcriptc.2908C>T p.Pro970Ser missense_variant 19/27 ENST00000683438.2 NP_001339115.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ANKS1BENST00000683438.2 linkuse as main transcriptc.2908C>T p.Pro970Ser missense_variant 19/27 NM_001352186.2 ENSP00000508105 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
249076
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135130
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000443
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000595
AC:
87
AN:
1461598
Hom.:
0
Cov.:
31
AF XY:
0.0000646
AC XY:
47
AN XY:
727068
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000765
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000827
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 26, 2022The c.2908C>T (p.P970S) alteration is located in exon 19 (coding exon 19) of the ANKS1B gene. This alteration results from a C to T substitution at nucleotide position 2908, causing the proline (P) at amino acid position 970 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Benign
0.0022
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.080
T;.;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.0
L;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.1
N;N;N
REVEL
Benign
0.22
Sift
Benign
0.35
T;T;T
Sift4G
Benign
0.71
T;T;T
Polyphen
1.0
D;D;B
Vest4
0.67
MVP
0.57
MPC
2.1
ClinPred
0.63
D
GERP RS
5.1
Varity_R
0.15
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs771639722; hg19: chr12-99223110; COSMIC: COSV59124493; COSMIC: COSV59124493; API