16-81020167-A-T

Variant names:

• chr16-81020167-A-T
• rs188630970
• NM_001100624.3:c.422A>T

Variant summary

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

The NM_001100624.3(CENPN):​c.422A>T​(p.Tyr141Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,022 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 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CENPN NM_001100624.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87
• Publications: 0 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]

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

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=0.045584142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPN	NM_001100624.3	c.422A>T	p.Tyr141Phe	missense_variant	Exon 6 of 11	ENST00000305850.10	NP_001094094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPN	ENST00000305850.10	c.422A>T	p.Tyr141Phe	missense_variant	Exon 6 of 11	1	NM_001100624.3	ENSP00000305608.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251382 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461830 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74400

African (AFR) AF: 0.0000481 AC: 2 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422A>T (p.Y141F) alteration is located in exon 6 (coding exon 5) of the CENPN gene. This alteration results from a A to T substitution at nucleotide position 422, causing the tyrosine (Y) at amino acid position 141 to be replaced by a phenylalanine (F). 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	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.016	T;.;.;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.046	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;M;.;M;M;.
PhyloP100		2.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.64	T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T
Polyphen		0.87	P;P;.;.;.;.
Vest4		0.43
MVP		0.33
MPC		0.070
ClinPred		0.26	T
GERP RS		3.4
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.18

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: rs188630970; hg19: chr16-81053772;