rs8131693

Variant names:

• chr21-46430193-G-A
• rs8131693
• NM_006031.6:c.7874G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46430193-G-A
• chr21-46430193-G-C
• chr21-46430193-G-T

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.7874G>A​(p.Arg2625Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,800 control chromosomes in the GnomAD database, including 1,773 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2625W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.061 (901 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (872 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.08
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037869215).
• BP6: Variant 21-46430193-G-A is Benign according to our data. Variant chr21-46430193-G-A is described in ClinVar as Benign. ClinVar VariationId is 138607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 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.7874G>A	p.Arg2625Gln	missense	Exon 36 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7520G>A	p.Arg2507Gln	missense	Exon 36 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.7874G>A	p.Arg2625Gln	missense	Exon 36 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.7520G>A	p.Arg2507Gln	missense	Exon 36 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.7907G>A	p.Arg2636Gln	missense	Exon 37 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 9201 AN: 152144 Hom.: 901 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0159 AC: 3983 AN: 251160 AF XY: 0.0116

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00995

GnomAD4 exome AF: 0.00684 AC: 10003 AN: 1461538 Hom.: 872 Cov.: 32 AF XY: 0.00592 AC XY: 4307 AN XY: 727082

African (AFR) AF: 0.221 AC: 7397 AN: 33462

American (AMR) AF: 0.0139 AC: 623 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86242

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53326

Middle Eastern (MID) AF: 0.0151 AC: 86 AN: 5700

European-Non Finnish (NFE) AF: 0.000818 AC: 909 AN: 1111900

Other (OTH) AF: 0.0154 AC: 932 AN: 60364

GnomAD4 genome AF: 0.0605 AC: 9213 AN: 152262 Hom.: 901 Cov.: 33 AF XY: 0.0586 AC XY: 4362 AN XY: 74440

African (AFR) AF: 0.207 AC: 8612 AN: 41528

American (AMR) AF: 0.0275 AC: 421 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68016

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0201 Hom.: 661

Bravo AF: 0.0684

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.200 AC: 879

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0191 AC: 2313

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.3
DANN	Benign	0.91
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.5	N
PhyloP100		2.1
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.048
Sift	Benign	0.18	T
Sift4G	Benign	0.59	T
Polyphen		0.024	B
Vest4		0.023
MPC		0.094
ClinPred		0.0027	T
GERP RS		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.018
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8131693; hg19: chr21-47850107;