chr12-98781200-A-G

Variant names:

• chr12-98781200-A-G
• NM_001352186.2:c.3358T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001352186.2(ANKS1B):​c.3358T>C​(p.Ser1120Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,418,056 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: 0.0000042 (0 hom.)
• Consequence: ANKS1B NM_001352186.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352186.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKS1B	NM_001352186.2	MANE Select	c.3358T>C	p.Ser1120Pro	missense	Exon 24 of 27	NP_001339115.1	A0A804HKX1
	ANKS1B	NM_001352188.1		c.3355T>C	p.Ser1119Pro	missense	Exon 24 of 27	NP_001339117.1
	ANKS1B	NM_001352187.1		c.3283T>C	p.Ser1095Pro	missense	Exon 23 of 26	NP_001339116.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKS1B	ENST00000683438.2	MANE Select	c.3358T>C	p.Ser1120Pro	missense	Exon 24 of 27	ENSP00000508105.1	A0A804HKX1
	ANKS1B	ENST00000547776.6	TSL:1	c.3283T>C	p.Ser1095Pro	missense	Exon 23 of 26	ENSP00000449629.2	Q7Z6G8-1
	ANKS1B	ENST00000547010.5	TSL:1	c.1831T>C	p.Ser611Pro	missense	Exon 15 of 18	ENSP00000448512.1	Q7Z6G8-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000423 AC: 6 AN: 1418056 Hom.: 0 Cov.: 27 AF XY: 0.00000712 AC XY: 5 AN XY: 702150

African (AFR) AF: 0.00 AC: 0 AN: 32724

American (AMR) AF: 0.00 AC: 0 AN: 39050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25394

East Asian (EAS) AF: 0.00 AC: 0 AN: 38474

South Asian (SAS) AF: 0.00 AC: 0 AN: 80974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000553 AC: 6 AN: 1085896

Other (OTH) AF: 0.00 AC: 0 AN: 58836

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.49
Sift	Benign	0.057	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.57		Loss of MoRF binding (P = 0.0572)
MVP		0.65
MPC		2.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.74
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-99174978;