chr15-40389508-A-G

Position:

• chr15-40389508-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000249776.13(KNSTRN):​c.488A>G​(p.Tyr163Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,724 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KNSTRN ENST00000249776.13 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.551

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]

ACMG classification

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=0.17697385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNSTRN	NM_033286.4	c.488A>G	p.Tyr163Cys	missense_variant, splice_region_variant	5/9	ENST00000249776.13	NP_150628.3
KNSTRN	NM_001142761.1	c.488A>G	p.Tyr163Cys	missense_variant, splice_region_variant	5/9		NP_001136233.1
KNSTRN	NM_001142762.1	c.488A>G	p.Tyr163Cys	missense_variant, splice_region_variant	5/8		NP_001136234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNSTRN	ENST00000249776.13	c.488A>G	p.Tyr163Cys	missense_variant, splice_region_variant	5/9	1	NM_033286.4	ENSP00000249776.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459724 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726328

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: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000530 Hom.: 0

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

Dec 06, 2022

The c.488A>G (p.Y163C) alteration is located in exon 5 (coding exon 5) of the KNSTRN gene. This alteration results from a A to G substitution at nucleotide position 488, causing the tyrosine (Y) at amino acid position 163 to be replaced by a cysteine (C). 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	0.097
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	.;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.8	D;D;D;.
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.23
MutPred		0.25		Loss of MoRF binding (P = 0.1011);Loss of MoRF binding (P = 0.1011);Loss of MoRF binding (P = 0.1011);.;
MVP		0.26
MPC		0.30
ClinPred		0.61	D
GERP RS		1.3
Varity_R		0.13
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1889961555; hg19: chr15-40681709;