1-46551185-G-A

Variant names:

• chr1-46551185-G-A
• rs780686467
• NM_001322255.2:c.31C>T

Variant summary

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

The NM_001322255.2(KNCN):​c.31C>T​(p.Arg11Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,457,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KNCN NM_001322255.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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

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=0.23423493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2	c.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 4	ENST00000481882.7	NP_001309184.1
KNCN	NM_001097611.1	c.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 3		NP_001091080.1
MKNK1-AS1	NR_038403.1	n.255-7040G>A		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7	c.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 4	5	NM_001322255.2	ENSP00000419705.3
KNCN	ENST00000396314.3	c.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 3	4		ENSP00000379607.3
MKNK1-AS1	ENST00000602433.1	n.255-7040G>A		intron_variant	Intron 3 of 7	2
MKNK1-AS1	ENST00000657773.1	n.260-7040G>A		intron_variant	Intron 2 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000820 AC: 2 AN: 243842 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132714

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1457820 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31C>T (p.R11C) alteration is located in exon 1 (coding exon 1) of the KNCN gene. This alteration results from a C to T substitution at nucleotide position 31, causing the arginine (R) at amino acid position 11 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	0.11
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.66	T
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.0070	.;B
Vest4		0.28
MutPred		0.29		Loss of disorder (P = 0.033);Loss of disorder (P = 0.033);
MVP		0.38
MPC		0.53
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs780686467; hg19: chr1-47016857; COSMIC: COSV99606382; COSMIC: COSV99606382;