Variant 15-40383275-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033286.4(KNSTRN):c.257T>A(p.Val86Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,766 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: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

KNSTRN
NM_033286.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.734

Variant links:

Genes affected

KNSTRN (HGNC:30767): (kinetochore localized astrin (SPAG5) binding protein) Enables microtubule plus-end binding activity and protein homodimerization activity. Involved in several processes, including cellular response to epidermal growth factor stimulus; mitotic sister chromatid segregation; and regulation of attachment of spindle microtubules to kinetochore. Located in several cellular components, including kinetochore; microtubule cytoskeleton; and ruffle. Implicated in actinic keratosis and skin squamous cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

KNSTRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17531905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KNSTRN	NM_033286.4 linkuse as main transcript	c.257T>A	p.Val86Glu	missense_variant	2/9	ENST00000249776.13	NP_150628.3
KNSTRN	NM_001142761.1 linkuse as main transcript	c.257T>A	p.Val86Glu	missense_variant	2/9		NP_001136233.1
KNSTRN	NM_001142762.1 linkuse as main transcript	c.257T>A	p.Val86Glu	missense_variant	2/8		NP_001136234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNSTRN	ENST00000249776.13 linkuse as main transcript	c.257T>A	p.Val86Glu	missense_variant	2/9	1	NM_033286.4	ENSP00000249776	P1	Q9Y448-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

248742

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

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:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000962

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000107

AC:

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

Oct 26, 2022

The c.257T>A (p.V86E) alteration is located in exon 2 (coding exon 2) of the KNSTRN gene. This alteration results from a T to A substitution at nucleotide position 257, causing the valine (V) at amino acid position 86 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

0.27

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.10

.;T;.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.0

D;D;D;.

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

0.94

P;P;D;.

Vest4

0.72

MutPred

0.39

Gain of ubiquitination at K84 (P = 0.0353);Gain of ubiquitination at K84 (P = 0.0353);Gain of ubiquitination at K84 (P = 0.0353);.;

MVP

0.17

MPC

0.80

ClinPred

0.15

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.24

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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