12-99244388-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001352186.2(ANKS1B):c.2373T>G(p.Asp791Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKS1B NM_001352186.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ANKS1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.25217783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKS1B	NM_001352186.2	c.2373T>G	p.Asp791Glu	missense_variant	14/27	ENST00000683438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKS1B	ENST00000683438.2	c.2373T>G	p.Asp791Glu	missense_variant	14/27		NM_001352186.2	P1
ANKS1B	ENST00000547776.6	c.2373T>G	p.Asp791Glu	missense_variant	14/26	1
ANKS1B	ENST00000547010.5	c.1113T>G	p.Asp371Glu	missense_variant	7/18	1
ANKS1B	ENST00000550778.5	c.189T>G	p.Asp63Glu	missense_variant	2/14	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454850 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000233

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.2373T>G (p.D791E) alteration is located in exon 14 (coding exon 14) of the ANKS1B gene. This alteration results from a T to G substitution at nucleotide position 2373, causing the aspartic acid (D) at amino acid position 791 to be replaced by a glutamic acid (E). 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	Benign	0.29
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.0019
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.081
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.92	P;D
Vest4		0.54
MutPred		0.27		Gain of catalytic residue at I790 (P = 0.0823);.;
MVP		0.46
MPC		0.23
ClinPred		0.93	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-99638166;