NM_006031.6:c.7074T>C

Variant names:

• chr21-46422019-T-C
• rs61735815
• NM_006031.6:c.7074T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.7074T>C​(p.Pro2358Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,613,906 control chromosomes in the GnomAD database, including 2,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (222 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2533 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.31
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 21-46422019-T-C is Benign according to our data. Variant chr21-46422019-T-C is described in ClinVar as Benign. ClinVar VariationId is 138629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0622 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.7074T>C	p.Pro2358Pro	synonymous	Exon 32 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6720T>C	p.Pro2240Pro	synonymous	Exon 32 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.7074T>C	p.Pro2358Pro	synonymous	Exon 32 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6720T>C	p.Pro2240Pro	synonymous	Exon 32 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.7107T>C	p.Pro2369Pro	synonymous	Exon 33 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7212 AN: 152142 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.0847

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0493

GnomAD2 exomes AF: 0.0460 AC: 11551 AN: 251150 AF XY: 0.0455

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0722

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0621

Gnomad OTH exome AF: 0.0512

GnomAD4 exome AF: 0.0552 AC: 80716 AN: 1461646 Hom.: 2533 Cov.: 32 AF XY: 0.0542 AC XY: 39392 AN XY: 727134

African (AFR) AF: 0.0225 AC: 752 AN: 33478

American (AMR) AF: 0.0239 AC: 1070 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 1857 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0136 AC: 1171 AN: 86258

European-Finnish (FIN) AF: 0.0833 AC: 4442 AN: 53296

Middle Eastern (MID) AF: 0.0322 AC: 186 AN: 5768

European-Non Finnish (NFE) AF: 0.0613 AC: 68154 AN: 1111902

Other (OTH) AF: 0.0510 AC: 3081 AN: 60386

GnomAD4 genome AF: 0.0474 AC: 7210 AN: 152260 Hom.: 222 Cov.: 33 AF XY: 0.0468 AC XY: 3487 AN XY: 74442

African (AFR) AF: 0.0250 AC: 1040 AN: 41556

American (AMR) AF: 0.0332 AC: 508 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4832

European-Finnish (FIN) AF: 0.0847 AC: 898 AN: 10600

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4337 AN: 68014

Other (OTH) AF: 0.0488 AC: 103 AN: 2112

Alfa AF: 0.0572 Hom.: 169

Bravo AF: 0.0429

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0559

EpiControl AF: 0.0555

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.052
DANN	Benign	0.47
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs61735815; hg19: chr21-47841933; COSMIC: COSV64033646; COSMIC: COSV64033646;