NM_006031.6:c.6819G>A

Variant names:

• chr21-46416737-G-A
• rs200610141
• NM_006031.6:c.6819G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006031.6(PCNT):​c.6819G>A​(p.Gly2273Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,596,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.254
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Moyamoya disease

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-46416737-G-A is Benign according to our data. Variant chr21-46416737-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211874.
• BP7: Synonymous conserved (PhyloP=-0.254 with no splicing effect.

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.6819G>A	p.Gly2273Gly	synonymous	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6465G>A	p.Gly2155Gly	synonymous	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.6819G>A	p.Gly2273Gly	synonymous	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6465G>A	p.Gly2155Gly	synonymous	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6852G>A	p.Gly2284Gly	synonymous	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000162 AC: 38 AN: 234138 AF XY: 0.000188

Gnomad AFR exome AF: 0.0000689

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0000504

Gnomad NFE exome AF: 0.000324

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000385 AC: 556 AN: 1444038 Hom.: 0 Cov.: 34 AF XY: 0.000371 AC XY: 266 AN XY: 716180

African (AFR) AF: 0.0000903 AC: 3 AN: 33236

American (AMR) AF: 0.0000228 AC: 1 AN: 43822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 84474

European-Finnish (FIN) AF: 0.0000394 AC: 2 AN: 50770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.000470 AC: 518 AN: 1102140

Other (OTH) AF: 0.000537 AC: 32 AN: 59564

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74464

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68026

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

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.72
DANN	Benign	0.53
PhyloP100		-0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200610141; hg19: chr21-47836651;