chr21-46443816-G-T

Variant names:

• chr21-46443816-G-T
• rs113591604
• NM_006031.6:c.9707G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006031.6(PCNT):​c.9707G>T​(p.Arg3236Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,436 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3236Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07248485).

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.9707G>T	p.Arg3236Leu	missense	Exon 45 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.9116G>T	p.Arg3039Leu	missense	Exon 45 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.9707G>T	p.Arg3236Leu	missense	Exon 45 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.9116G>T	p.Arg3039Leu	missense	Exon 45 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.9740G>T	p.Arg3247Leu	missense	Exon 46 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461436 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5444

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.4
DANN	Benign	0.86
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.95	L
PhyloP100		0.0060
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.053
Sift	Benign	0.33	T
Sift4G	Uncertain	0.051	T
Polyphen		0.0030	B
Vest4		0.082
MutPred		0.31		Loss of solvent accessibility (P = 0.0022)
MVP		0.24
MPC		0.36
ClinPred		0.19	T
GERP RS		-0.84
Varity_R		0.053
gMVP		0.36
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs113591604; hg19: chr21-47863729;