12-122562638-G-C

Variant names:

• chr12-122562638-G-C
• rs773891168
• NM_014708.6:c.1543G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014708.6(KNTC1):​c.1543G>C​(p.Val515Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V515M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KNTC1 NM_014708.6 missense, splice_region
• Scores: Splicing: ADA: 0.7786
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

Genes affected

KNTC1 (HGNC:17255): (kinetochore associated 1) This gene encodes a protein that is one of many involved in mechanisms to ensure proper chromosome segregation during cell division. Experimental evidence indicated that the encoded protein functioned in a similar manner to that of the Drosophila rough deal protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4021227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNTC1	NM_014708.6	c.1543G>C	p.Val515Leu	missense_variant, splice_region_variant	Exon 20 of 64	ENST00000333479.12	NP_055523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNTC1	ENST00000333479.12	c.1543G>C	p.Val515Leu	missense_variant, splice_region_variant	Exon 20 of 64	1	NM_014708.6	ENSP00000328236.6
KNTC1	ENST00000450485.6	c.1432G>C	p.Val478Leu	missense_variant, splice_region_variant	Exon 19 of 39	2		ENSP00000397992.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;M
PhyloP100		2.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.80	P;D
Vest4		0.62
MutPred		0.38		.;Loss of ubiquitination at K513 (P = 0.1202);
MVP		0.34
MPC		0.038
ClinPred		0.91	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.39
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.68
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

Other links and lift over

dbSNP: rs773891168; hg19: chr12-123047185;