rs17371795

Variant names:

• chr21-46435963-A-G
• rs17371795
• NM_006031.6:c.8811A>G

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.8811A>G​(p.Thr2937Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,614,024 control chromosomes in the GnomAD database, including 13,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1192 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12745 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.80
• Publications: 23 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=-0.93).
• BP6: Variant 21-46435963-A-G is Benign according to our data. Variant chr21-46435963-A-G is described in ClinVar as Benign. ClinVar VariationId is 95343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 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.8811A>G	p.Thr2937Thr	synonymous	Exon 39 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8220A>G	p.Thr2740Thr	synonymous	Exon 39 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.8811A>G	p.Thr2937Thr	synonymous	Exon 39 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.8220A>G	p.Thr2740Thr	synonymous	Exon 39 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.8844A>G	p.Thr2948Thr	synonymous	Exon 40 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18024 AN: 152154 Hom.: 1193 Cov.: 33

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.142 AC: 35715 AN: 251106 AF XY: 0.146

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.190

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.127 AC: 185224 AN: 1461752 Hom.: 12745 Cov.: 34 AF XY: 0.130 AC XY: 94552 AN XY: 727192

African (AFR) AF: 0.0662 AC: 2218 AN: 33480

American (AMR) AF: 0.160 AC: 7158 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2885 AN: 26134

East Asian (EAS) AF: 0.223 AC: 8842 AN: 39696

South Asian (SAS) AF: 0.203 AC: 17550 AN: 86256

European-Finnish (FIN) AF: 0.157 AC: 8393 AN: 53400

Middle Eastern (MID) AF: 0.164 AC: 948 AN: 5768

European-Non Finnish (NFE) AF: 0.117 AC: 129581 AN: 1111904

Other (OTH) AF: 0.127 AC: 7649 AN: 60390

GnomAD4 genome AF: 0.118 AC: 18044 AN: 152272 Hom.: 1192 Cov.: 33 AF XY: 0.124 AC XY: 9257 AN XY: 74442

African (AFR) AF: 0.0660 AC: 2745 AN: 41582

American (AMR) AF: 0.157 AC: 2402 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1038 AN: 5140

South Asian (SAS) AF: 0.199 AC: 963 AN: 4828

European-Finnish (FIN) AF: 0.158 AC: 1676 AN: 10606

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8320 AN: 68014

Other (OTH) AF: 0.115 AC: 244 AN: 2116

Alfa AF: 0.118 Hom.: 1775

Bravo AF: 0.114

Asia WGS AF: 0.203 AC: 704 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.93
CADD	Benign	0.40
DANN	Benign	0.37
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17371795; hg19: chr21-47855876; COSMIC: COSV64028891; COSMIC: COSV64028891;