1-46547749-C-A

Variant names:

• chr1-46547749-C-A
• rs934257082
• NM_001322255.2:c.356G>T

Variant summary

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

The NM_001322255.2(KNCN):​c.356G>T​(p.Arg119Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,331,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. R119Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: KNCN NM_001322255.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

Genes affected

KNCN (HGNC:26488): (kinocilin) Predicted to be located in apical part of cell; cytoplasm; and microtubule cytoskeleton. Predicted to be active in several cellular components, including apical plasma membrane; cytoskeleton; and kinocilium. [provided by Alliance of Genome Resources, Apr 2022]

MKNK1-AS1 (HGNC:44129): (MKNK1 antisense RNA 1)

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=0.27282333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2	c.356G>T	p.Arg119Leu	missense_variant	Exon 4 of 4	ENST00000481882.7	NP_001309184.1
KNCN	NM_001097611.1	c.287G>T	p.Arg96Leu	missense_variant	Exon 3 of 3		NP_001091080.1
MKNK1-AS1	NR_038403.1	n.254+3981C>A		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7	c.356G>T	p.Arg119Leu	missense_variant	Exon 4 of 4	5	NM_001322255.2	ENSP00000419705.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000375 AC: 5 AN: 1331624 Hom.: 0 Cov.: 31 AF XY: 0.00000308 AC XY: 2 AN XY: 650276

African (AFR) AF: 0.00 AC: 0 AN: 29412

American (AMR) AF: 0.00 AC: 0 AN: 25022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19994

East Asian (EAS) AF: 0.00 AC: 0 AN: 35590

South Asian (SAS) AF: 0.00 AC: 0 AN: 66578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00000476 AC: 5 AN: 1049586

Other (OTH) AF: 0.00 AC: 0 AN: 54976

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.67	.;P
Vest4		0.50
MutPred		0.25		.;Loss of MoRF binding (P = 0.0015);
MVP		0.040
MPC		0.12
ClinPred		0.53	D
GERP RS		2.8
Varity_R		0.14
gMVP		0.045
Mutation Taster		=79/21	polymorphism

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: rs934257082; hg19: chr1-47013421;