Variant 15-40382906-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_033286.4(KNSTRN):c.71C>A(p.Ser24Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S24F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

KNSTRN
NM_033286.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.169

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-40382906-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376441.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.08082119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KNSTRN	NM_033286.4 linkuse as main transcript	c.71C>A	p.Ser24Tyr	missense_variant	1/9	ENST00000249776.13
KNSTRN	NM_001142761.1 linkuse as main transcript	c.71C>A	p.Ser24Tyr	missense_variant	1/9
KNSTRN	NM_001142762.1 linkuse as main transcript	c.71C>A	p.Ser24Tyr	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNSTRN	ENST00000249776.13 linkuse as main transcript	c.71C>A	p.Ser24Tyr	missense_variant	1/9	1	NM_033286.4	P1	Q9Y448-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

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:

0.000193

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0030

.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.66

T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.081

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.063

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.70

P;P;P

Vest4

0.18

MutPred

0.23

Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);

MVP

0.14

MPC

0.35

ClinPred

0.25

GERP RS

0.10

Varity_R

0.086

gMVP

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over