rs61735825

Variant names:

• chr21-46334596-A-G
• rs61735825
• NM_006031.6:c.467A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006031.6(PCNT):​c.467A>G​(p.His156Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 139,726 control chromosomes in the GnomAD database, including 1 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H156Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (62 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.595
• Publications: 12 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003022194).
• BP6: Variant 21-46334596-A-G is Benign according to our data. Variant chr21-46334596-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159608.

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.467A>G	p.His156Arg	missense	Exon 3 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.113A>G	p.His38Arg	missense	Exon 3 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.467A>G	p.His156Arg	missense	Exon 3 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.113A>G	p.His38Arg	missense	Exon 3 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.467A>G	p.His156Arg	missense	Exon 3 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 194 AN: 139612 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000425

Gnomad ASJ AF: 0.000905

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.000427

Gnomad FIN AF: 0.000696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00156

GnomAD2 exomes AF: 0.00138 AC: 330 AN: 238690 AF XY: 0.00130

Gnomad AFR exome AF: 0.000636

Gnomad AMR exome AF: 0.000632

Gnomad ASJ exome AF: 0.000926

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000812

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00206

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00617 AC: 8203 AN: 1330044 Hom.: 62 Cov.: 32 AF XY: 0.00580 AC XY: 3846 AN XY: 663618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00148 AC: 48 AN: 32382

American (AMR) AF: 0.00374 AC: 159 AN: 42546

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 57 AN: 24684

East Asian (EAS) AF: 0.000329 AC: 13 AN: 39496

South Asian (SAS) AF: 0.000445 AC: 38 AN: 85328

European-Finnish (FIN) AF: 0.00138 AC: 70 AN: 50892

Middle Eastern (MID) AF: 0.000888 AC: 5 AN: 5632

European-Non Finnish (NFE) AF: 0.00762 AC: 7568 AN: 993640

Other (OTH) AF: 0.00442 AC: 245 AN: 55444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00140 AC: 195 AN: 139726 Hom.: 1 Cov.: 33 AF XY: 0.00131 AC XY: 90 AN XY: 68688

African (AFR) AF: 0.00156 AC: 61 AN: 39128

American (AMR) AF: 0.000425 AC: 6 AN: 14134

Ashkenazi Jewish (ASJ) AF: 0.000905 AC: 3 AN: 3314

East Asian (EAS) AF: 0.000393 AC: 2 AN: 5086

South Asian (SAS) AF: 0.000428 AC: 2 AN: 4676

European-Finnish (FIN) AF: 0.000696 AC: 7 AN: 10054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00184 AC: 111 AN: 60208

Other (OTH) AF: 0.00154 AC: 3 AN: 1948

Alfa AF: 0.0456 Hom.: 58

Bravo AF: 0.0376

TwinsUK AF: 0.0467 AC: 173

ALSPAC AF: 0.0488 AC: 188

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0370 AC: 318

ExAC AF: 0.000556 AC: 67

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.23
DANN	Benign	0.31
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00062	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.59
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.023
Sift	Benign	0.45	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.084
MVP		0.20
MPC		0.099
ClinPred		0.0013	T
GERP RS		0.16
Varity_R		0.025
gMVP		0.015
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: rs61735825; hg19: chr21-47754510; COSMIC: COSV64028541;