rs140398533

Variant names:

• chr21-46412027-C-T
• rs140398533
• NM_006031.6:c.5954C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-46412027-C-T
• chr21-46412027-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006031.6(PCNT):​c.5954C>T​(p.Ser1985Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,608,432 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1985S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 34)
  • Exomes 𝑓: 0.00056 (4 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0400
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003622055).
• BP6: Variant 21-46412027-C-T is Benign according to our data. Variant chr21-46412027-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211868.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00533 (812/152368) while in subpopulation AFR AF = 0.0187 (779/41592). AF 95% confidence interval is 0.0176. There are 6 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.5954C>T	p.Ser1985Phe	missense	Exon 28 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5600C>T	p.Ser1867Phe	missense	Exon 28 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.5954C>T	p.Ser1985Phe	missense	Exon 28 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.5600C>T	p.Ser1867Phe	missense	Exon 28 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.5987C>T	p.Ser1996Phe	missense	Exon 29 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152250 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00154 AC: 365 AN: 237120 AF XY: 0.00105

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000957

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000556 AC: 810 AN: 1456064 Hom.: 4 Cov.: 34 AF XY: 0.000451 AC XY: 327 AN XY: 724604

African (AFR) AF: 0.0201 AC: 672 AN: 33432

American (AMR) AF: 0.00121 AC: 54 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48854

Middle Eastern (MID) AF: 0.000598 AC: 3 AN: 5016

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111808

Other (OTH) AF: 0.00121 AC: 73 AN: 60242

GnomAD4 genome AF: 0.00533 AC: 812 AN: 152368 Hom.: 6 Cov.: 34 AF XY: 0.00497 AC XY: 370 AN XY: 74508

African (AFR) AF: 0.0187 AC: 779 AN: 41592

American (AMR) AF: 0.00163 AC: 25 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000819 Hom.: 3

Bravo AF: 0.00645

ESP6500AA AF: 0.0173 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Microcephalic osteodysplastic primordial dwarfism type II (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.6
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.040
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.043
Sift	Benign	0.037	D
Sift4G	Uncertain	0.051	T
Polyphen		0.42	B
Vest4		0.23
MVP		0.43
MPC		0.093
ClinPred		0.021	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.091
Mutation Taster		=99/1	polymorphism

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: rs140398533; hg19: chr21-47831941; COSMIC: COSV107464346;