rs4818842

Variant names:

• chr21-46438335-A-G
• rs4818842
• NM_006031.6:c.9271A>G

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.9271A>G​(p.Ser3091Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0256 in 1,613,794 control chromosomes in the GnomAD database, including 770 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3091R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (90 hom., cov: 33)
  • Exomes 𝑓: 0.026 (680 hom.)
• Consequence: PCNT NM_006031.6 missense, splice_region
• Scores: Splicing: ADA: 0.2499
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.79
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025025606).
• BP6: Variant 21-46438335-A-G is Benign according to our data. Variant chr21-46438335-A-G is described in ClinVar as Benign. ClinVar VariationId is 138614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0716 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.9271A>G	p.Ser3091Gly	missense splice_region	Exon 41 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8680A>G	p.Ser2894Gly	missense splice_region	Exon 41 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.9271A>G	p.Ser3091Gly	missense splice_region	Exon 41 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.8680A>G	p.Ser2894Gly	missense splice_region	Exon 41 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.9304A>G	p.Ser3102Gly	missense splice_region	Exon 42 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3841 AN: 152194 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0336 AC: 8447 AN: 251206 AF XY: 0.0313

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00283

Gnomad FIN exome AF: 0.0422

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0256 AC: 37476 AN: 1461482 Hom.: 680 Cov.: 31 AF XY: 0.0255 AC XY: 18564 AN XY: 727068

African (AFR) AF: 0.00394 AC: 132 AN: 33470

American (AMR) AF: 0.0991 AC: 4430 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 358 AN: 26132

East Asian (EAS) AF: 0.00582 AC: 231 AN: 39700

South Asian (SAS) AF: 0.0210 AC: 1810 AN: 86240

European-Finnish (FIN) AF: 0.0408 AC: 2177 AN: 53406

Middle Eastern (MID) AF: 0.00910 AC: 52 AN: 5714

European-Non Finnish (NFE) AF: 0.0242 AC: 26935 AN: 1111722

Other (OTH) AF: 0.0224 AC: 1351 AN: 60380

GnomAD4 genome AF: 0.0252 AC: 3843 AN: 152312 Hom.: 90 Cov.: 33 AF XY: 0.0269 AC XY: 2002 AN XY: 74468

African (AFR) AF: 0.00483 AC: 201 AN: 41582

American (AMR) AF: 0.0752 AC: 1151 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5170

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4826

European-Finnish (FIN) AF: 0.0434 AC: 461 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1758 AN: 68026

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0246 Hom.: 190

Bravo AF: 0.0267

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0235 AC: 202

ExAC AF: 0.0307 AC: 3726

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0201

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.069
Sift	Benign	0.20	T
Sift4G	Benign	0.072	T
Polyphen		0.82	P
Vest4		0.037
MPC		0.21
ClinPred		0.028	T
GERP RS		5.0
Varity_R		0.062
gMVP		0.028
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.15		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: rs4818842; hg19: chr21-47858248;