16-81020233-C-T

Variant names:

• chr16-81020233-C-T
• rs145304481
• NM_001100624.3:c.488C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001100624.3(CENPN):​c.488C>T​(p.Thr163Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CENPN NM_001100624.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.163
• Publications: 2 publications found

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]

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049038142).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100624.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPN	NM_001100624.3	MANE Select	c.488C>T	p.Thr163Met	missense	Exon 6 of 11	NP_001094094.2	Q96H22-1
	CENPN	NM_001100625.3		c.488C>T	p.Thr163Met	missense	Exon 6 of 11	NP_001094095.2	Q96H22-3
	CENPN	NM_001270473.2		c.428C>T	p.Thr143Met	missense	Exon 5 of 10	NP_001257402.1	Q96H22-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPN	ENST00000305850.10	TSL:1 MANE Select	c.488C>T	p.Thr163Met	missense	Exon 6 of 11	ENSP00000305608.5	Q96H22-1
	CENPN	ENST00000299572.9	TSL:1	c.488C>T	p.Thr163Met	missense	Exon 6 of 7	ENSP00000299572.5	Q96H22-2
	CMC2	ENST00000565914.5	TSL:3	c.-161G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000455723.1	Q9NRP2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 251156 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000123

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: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461750 Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 89 AN XY: 727190

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1111954

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74326

African (AFR) AF: 0.000121 AC: 5 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000778 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.97
DANN	Benign	0.82
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.16
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.21
Sift	Benign	0.060	T
Sift4G	Uncertain	0.020	D
Polyphen		0.034	B
Vest4		0.39
MVP		0.072
MPC		0.013
ClinPred		0.024	T
GERP RS		-7.3
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.36
Mutation Taster		=91/9	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: rs145304481; hg19: chr16-81053838; COSMIC: COSV100001413; COSMIC: COSV100001413;