Variant 12-98798993-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001352211.2(ANKS1B):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ANKS1B
NM_001352211.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34

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]

ANKS1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKS1B	NM_001352186.2 linkuse as main transcript	c.3283A>G	p.Met1095Val	missense_variant	22/27	ENST00000683438.2	NP_001339115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKS1B	ENST00000683438.2 linkuse as main transcript	c.3283A>G	p.Met1095Val	missense_variant	22/27		NM_001352186.2	ENSP00000508105.1		A0A804HKX1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242096

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000576

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1452172

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722262

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:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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 submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.3208A>G (p.M1070V) alteration is located in exon 21 (coding exon 21) of the ANKS1B gene. This alteration results from a A to G substitution at nucleotide position 3208, causing the methionine (M) at amino acid position 1070 to be replaced by a valine (V). 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

Uncertain

0.54

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;.;T;.;.;.;.;.;.;.;.;T;.;T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.59

.;.;N;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.4

N;D;N;N;N;N;D;N;N;D;N;.;.;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.068

T;T;D;T;T;T;T;T;T;T;T;.;.;.;.

Sift4G

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T;D;.;D;.

Polyphen

0.0070, 0.93, 0.057, 0.94, 0.77, 0.034, 0.20

.;B;P;B;P;.;P;.;P;B;B;.;.;.;.

Vest4

0.66

MutPred

0.55

.;.;Gain of catalytic residue at Y1066 (P = 0.015);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.66

MPC

1.9

ClinPred

0.71

GERP RS

5.9

Varity_R

0.44

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over