chr16-81020104-C-A

Position:

• chr16-81020104-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100624.3(CENPN):​c.359C>A​(p.Thr120Lys) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CENPN NM_001100624.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.784

Genes affected

CENPN (HGNC:30873): (centromere protein N) The protein encoded by this gene forms part of the nucleosome-associated complex and is important for kinetochore assembly. It is bound to kinetochores during S phase and G2 and recruits other proteins to the centromere. Pseudogenes of this gene are located on chromosome 2. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

CENPN-AS1 (HGNC:55106): (CENPN antisense RNA 1)

CMC2 (HGNC:24447): (C-X9-C motif containing 2) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39609218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPN	NM_001100624.3	c.359C>A	p.Thr120Lys	missense_variant	6/11	ENST00000305850.10
CENPN-AS1	XR_007065136.1	n.410-3069G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPN	ENST00000305850.10	c.359C>A	p.Thr120Lys	missense_variant	6/11	1	NM_001100624.3	P1
CENPN-AS1	ENST00000649061.1	n.634G>T		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 2 AN: 1445544 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000496

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.359C>A (p.T120K) alteration is located in exon 6 (coding exon 5) of the CENPN gene. This alteration results from a C to A substitution at nucleotide position 359, causing the threonine (T) at amino acid position 120 to be replaced by a lysine (K). 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	0.26
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.061	T;.;.;.;.;T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.86	D;T;T;D;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.40	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M;.
MutationTaster	Benign	0.77	N;N;N;N;N;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.037	D;D;D;T;D;D
Sift4G	Benign	0.079	T;T;T;T;T;T
Polyphen		0.62	P;P;.;.;.;.
Vest4		0.73
MutPred		0.68		Gain of MoRF binding (P = 0.0248);Gain of MoRF binding (P = 0.0248);.;Gain of MoRF binding (P = 0.0248);Gain of MoRF binding (P = 0.0248);Gain of MoRF binding (P = 0.0248);
MVP		0.50
MPC		0.045
ClinPred		0.92	D
GERP RS		1.1
Varity_R		0.26
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81053709;