1-46551161-C-T

Variant names:

• chr1-46551161-C-T
• rs1431056869
• NM_001322255.2:c.55G>A

Variant summary

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

The NM_001322255.2(KNCN):​c.55G>A​(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KNCN NM_001322255.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 4	ENST00000481882.7	NP_001309184.1
KNCN	NM_001097611.1	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 3		NP_001091080.1
MKNK1-AS1	NR_038403.1	n.255-7064C>T		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 4	5	NM_001322255.2	ENSP00000419705.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 244820 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55G>A (p.A19T) alteration is located in exon 1 (coding exon 1) of the KNCN gene. This alteration results from a G to A substitution at nucleotide position 55, causing the alanine (A) at amino acid position 19 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Benign	0.0023	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.056	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.49	T
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Benign	0.26
Sift	Benign	0.069	T;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.99	.;D
Vest4		0.48
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.74
MPC		0.43
ClinPred		0.86	D
GERP RS		4.5
PromoterAI		0.027	Neutral
Varity_R		0.10
gMVP		0.32
Mutation Taster		=94/6	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: rs1431056869; hg19: chr1-47016833; COSMIC: COSV53815828; COSMIC: COSV53815828;