NM_006031.6:c.7655G>A

Variant names:

• chr21-46428555-G-A
• rs199589423
• NM_006031.6:c.7655G>A

Variant summary

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

The NM_006031.6(PCNT):​c.7655G>A​(p.Arg2552His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,605,800 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R2552R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 1.32
• Publications: 1 publications found

Genes affected

PCNT (HGNC:16068): (pericentrin) The protein encoded by this gene binds to calmodulin and is expressed in the centrosome. It is an integral component of the pericentriolar material (PCM). The protein contains a series of coiled-coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The protein interacts with the microtubule nucleation component gamma-tubulin and is likely important to normal functioning of the centrosomes, cytoskeleton, and cell-cycle progression. Mutations in this gene cause Seckel syndrome-4 and microcephalic osteodysplastic primordial dwarfism type II. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PCNT Gene-Disease associations (from GenCC):

• microcephalic osteodysplastic primordial dwarfism type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.012868464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.7655G>A	p.Arg2552His	missense	Exon 35 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7301G>A	p.Arg2434His	missense	Exon 35 of 47	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.7655G>A	p.Arg2552His	missense	Exon 35 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.7301G>A	p.Arg2434His	missense	Exon 35 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.7688G>A	p.Arg2563His	missense	Exon 36 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152266 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000188 AC: 44 AN: 233900 AF XY: 0.000209

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.000383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000572

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000833 AC: 121 AN: 1453416 Hom.: 0 Cov.: 33 AF XY: 0.0000830 AC XY: 60 AN XY: 723158

African (AFR) AF: 0.00147 AC: 49 AN: 33408

American (AMR) AF: 0.000315 AC: 14 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85948

European-Finnish (FIN) AF: 0.0000210 AC: 1 AN: 47662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4916

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111232

Other (OTH) AF: 0.000250 AC: 15 AN: 60058

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152384 Hom.: 0 Cov.: 34 AF XY: 0.000577 AC XY: 43 AN XY: 74516

African (AFR) AF: 0.00180 AC: 75 AN: 41592

American (AMR) AF: 0.000718 AC: 11 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000510

ESP6500AA AF: 0.000685 AC: 3

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000216 AC: 26

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Microcephalic osteodysplastic primordial dwarfism type II (1)
-	-	1	PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.022
Sift	Benign	0.33	T
Sift4G	Benign	0.15	T
Polyphen		0.017	B
Vest4		0.21
MVP		0.33
MPC		0.11
ClinPred		0.0057	T
GERP RS		0.67
Varity_R		0.028
gMVP		0.032
Mutation Taster		=96/4	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: rs199589423; hg19: chr21-47848469; COSMIC: COSV64024809; COSMIC: COSV64024809;