rs369949793

Variant names:

• chr21-46428544-C-A
• rs369949793
• NM_006031.6:c.7644C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46428544-C-A
• chr21-46428544-C-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.7644C>A​(p.Ser2548Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2548S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• 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=0.23463595).

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.7644C>A	p.Ser2548Arg	missense	Exon 35 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7290C>A	p.Ser2430Arg	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.7644C>A	p.Ser2548Arg	missense	Exon 35 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.7290C>A	p.Ser2430Arg	missense	Exon 35 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.7677C>A	p.Ser2559Arg	missense	Exon 36 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455912 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724342

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000225 AC: 1 AN: 44536

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111384

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.67
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.081
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.25		Gain of MoRF binding (P = 0.013)
MVP		0.40
MPC		0.41
ClinPred		0.97	D
GERP RS		-4.7
Varity_R		0.30
gMVP		0.11
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: rs369949793; hg19: chr21-47848458;