15-40382906-C-T

Variant names:

• chr15-40382906-C-T
• rs868438023
• NM_033286.4:c.71C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033286.4(KNSTRN):​c.71C>T​(p.Ser24Phe) 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 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KNSTRN NM_033286.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169
• Publications: 21 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075208604).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033286.4. 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
	KNSTRN	NM_033286.4	MANE Select	c.71C>T	p.Ser24Phe	missense	Exon 1 of 9	NP_150628.3	Q9Y448-1
	KNSTRN	NM_001142761.1		c.71C>T	p.Ser24Phe	missense	Exon 1 of 9	NP_001136233.1	Q9Y448-2
	KNSTRN	NM_001142762.1		c.71C>T	p.Ser24Phe	missense	Exon 1 of 8	NP_001136234.1	Q9Y448-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNSTRN	ENST00000249776.13	TSL:1 MANE Select	c.71C>T	p.Ser24Phe	missense	Exon 1 of 9	ENSP00000249776.8	Q9Y448-1
	KNSTRN	ENST00000416151.6	TSL:3	c.71C>T	p.Ser24Phe	missense	Exon 1 of 9	ENSP00000391233.2	Q9Y448-2
	KNSTRN	ENST00000448395.6	TSL:2	c.71C>T	p.Ser24Phe	missense	Exon 1 of 8	ENSP00000393001.2	Q9Y448-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459954 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726270

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4176

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.17
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.061
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.53	P
Vest4		0.21
MutPred		0.26		Loss of disorder (P = 0.0055)
MVP		0.12
MPC		0.24
ClinPred		0.15	T
GERP RS		0.10
PromoterAI		0.026	Neutral
Varity_R		0.11
gMVP		0.058
Mutation Taster		=97/3	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs868438023; hg19: chr15-40675107; COSMIC: COSV51103508; COSMIC: COSV51103508;