16-81012064-G-A

Variant names:

• chr16-81012064-G-A
• rs144532651
• NM_001100624.3:c.125G>A

Variant summary

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

The NM_001100624.3(CENPN):​c.125G>A​(p.Arg42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,614,110 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: CENPN NM_001100624.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.282
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076358914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPN	NM_001100624.3	c.125G>A	p.Arg42Gln	missense_variant	Exon 2 of 11	ENST00000305850.10	NP_001094094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPN	ENST00000305850.10	c.125G>A	p.Arg42Gln	missense_variant	Exon 2 of 11	1	NM_001100624.3	ENSP00000305608.5

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152144 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251398 AF XY: 0.000265

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000187 AC: 274 AN: 1461846 Hom.: 1 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 727226

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111992

Other (OTH) AF: 0.000563 AC: 34 AN: 60394

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74452

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.000916 AC: 14 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000353 Hom.: 1

Bravo AF: 0.000431

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125G>A (p.R42Q) alteration is located in exon 2 (coding exon 1) of the CENPN gene. This alteration results from a G to A substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a glutamine (Q). 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	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.;.;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.062	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0076	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;.
PhyloP100		0.28
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.053	T;D;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.47	P;P;.;.;.;.
Vest4		0.22
MVP		0.31
MPC		0.014
ClinPred		0.026	T
GERP RS		1.4
Varity_R		0.15
gMVP		0.15
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144532651; hg19: chr16-81045669;