1-46547743-G-A

Variant names:

• chr1-46547743-G-A
• rs373537843
• NM_001322255.2:c.362C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001322255.2(KNCN):​c.362C>T​(p.Ala121Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,337,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. A121D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KNCN NM_001322255.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05768591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNCN	NM_001322255.2	c.362C>T	p.Ala121Val	missense_variant	Exon 4 of 4	ENST00000481882.7	NP_001309184.1
KNCN	NM_001097611.1	c.293C>T	p.Ala98Val	missense_variant	Exon 3 of 3		NP_001091080.1
MKNK1-AS1	NR_038403.1	n.254+3975G>A		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNCN	ENST00000481882.7	c.362C>T	p.Ala121Val	missense_variant	Exon 4 of 4	5	NM_001322255.2	ENSP00000419705.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1337564 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 653820

African (AFR) AF: 0.00 AC: 0 AN: 29652

American (AMR) AF: 0.00 AC: 0 AN: 26252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20444

East Asian (EAS) AF: 0.00 AC: 0 AN: 35596

South Asian (SAS) AF: 0.00 AC: 0 AN: 67636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4912

European-Non Finnish (NFE) AF: 9.51e-7 AC: 1 AN: 1051762

Other (OTH) AF: 0.0000181 AC: 1 AN: 55224

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.060
Sift	Benign	0.11	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.030	.;B
Vest4		0.038
MutPred		0.074		.;Gain of MoRF binding (P = 0.0932);
MVP		0.014
MPC		0.091
ClinPred		0.28	T
GERP RS		3.7
Varity_R		0.065
gMVP		0.031
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373537843; hg19: chr1-47013415;