rs34151633

Variant names:

• chr21-46416489-T-C
• rs34151633
• NM_006031.6:c.6571T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):​c.6571T>C​(p.Ser2191Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,614,058 control chromosomes in the GnomAD database, including 1,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2191Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.034 (147 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1597 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0120
• Publications: 12 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• Moyamoya disease

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026471317).
• BP6: Variant 21-46416489-T-C is Benign according to our data. Variant chr21-46416489-T-C is described in ClinVar as Benign. ClinVar VariationId is 159634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.6571T>C	p.Ser2191Pro	missense	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6217T>C	p.Ser2073Pro	missense	Exon 30 of 47	NP_001302458.1	O95613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.6571T>C	p.Ser2191Pro	missense	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6217T>C	p.Ser2073Pro	missense	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6604T>C	p.Ser2202Pro	missense	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5164 AN: 152216 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0369 AC: 9263 AN: 251262 AF XY: 0.0373

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.0493

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0412 AC: 60161 AN: 1461724 Hom.: 1597 Cov.: 34 AF XY: 0.0412 AC XY: 29941 AN XY: 727186

African (AFR) AF: 0.0166 AC: 557 AN: 33480

American (AMR) AF: 0.0310 AC: 1385 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 3856 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0184 AC: 1586 AN: 86258

European-Finnish (FIN) AF: 0.00873 AC: 465 AN: 53278

Middle Eastern (MID) AF: 0.0829 AC: 478 AN: 5768

European-Non Finnish (NFE) AF: 0.0442 AC: 49100 AN: 1111988

Other (OTH) AF: 0.0452 AC: 2730 AN: 60394

GnomAD4 genome AF: 0.0339 AC: 5162 AN: 152334 Hom.: 147 Cov.: 32 AF XY: 0.0315 AC XY: 2346 AN XY: 74486

African (AFR) AF: 0.0166 AC: 692 AN: 41584

American (AMR) AF: 0.0370 AC: 566 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 503 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4828

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10626

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0451 AC: 3070 AN: 68026

Other (OTH) AF: 0.0482 AC: 102 AN: 2116

Alfa AF: 0.0481 Hom.: 1355

Bravo AF: 0.0373

TwinsUK AF: 0.0413 AC: 153

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0560 AC: 482

ExAC AF: 0.0360 AC: 4367

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0589

EpiControl AF: 0.0580

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.012
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.025
Sift	Benign	0.25	T
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.097
MPC		0.34
ClinPred		0.0035	T
GERP RS		0.73
Varity_R		0.13
gMVP		0.15
Mutation Taster		=95/5	polymorphism (auto)

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: rs34151633; hg19: chr21-47836403; COSMIC: COSV64028289; COSMIC: COSV64028289;