rs61735823

Variant names:

• chr21-46334635-G-A
• rs61735823
• NM_006031.6:c.506G>A

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.506G>A​(p.Arg169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 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. R169C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.00300
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04049015).
• BP6: Variant 21-46334635-G-A is Benign according to our data. Variant chr21-46334635-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159616.

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.506G>A	p.Arg169His	missense	Exon 3 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.152G>A	p.Arg51His	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.506G>A	p.Arg169His	missense	Exon 3 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.152G>A	p.Arg51His	missense	Exon 3 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.506G>A	p.Arg169His	missense	Exon 3 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 43 AN: 137968 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000643

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.000416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00107

GnomAD2 exomes AF: 0.0000535 AC: 13 AN: 243186 AF XY: 0.0000304

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000144

Gnomad NFE exome AF: 0.0000548

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000503 AC: 72 AN: 1430710 Hom.: 0 Cov.: 33 AF XY: 0.0000646 AC XY: 46 AN XY: 711552

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

African (AFR) AF: 0.000186 AC: 6 AN: 32192

American (AMR) AF: 0.0000231 AC: 1 AN: 43370

Ashkenazi Jewish (ASJ) AF: 0.000162 AC: 4 AN: 24650

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39160

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83664

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.0000486 AC: 53 AN: 1091540

Other (OTH) AF: 0.0000340 AC: 2 AN: 58762

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000311 AC: 43 AN: 138084 Hom.: 0 Cov.: 33 AF XY: 0.000325 AC XY: 22 AN XY: 67626

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

African (AFR) AF: 0.000386 AC: 14 AN: 36290

American (AMR) AF: 0.000642 AC: 9 AN: 14028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3122

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.000439 AC: 2 AN: 4558

European-Finnish (FIN) AF: 0.000416 AC: 4 AN: 9604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000192 AC: 12 AN: 62376

Other (OTH) AF: 0.00106 AC: 2 AN: 1886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00444 Hom.: 0

ExAC AF: 0.00119 AC: 144

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.91
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.0030
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.088
Sift	Benign	0.086	T
Sift4G	Benign	0.097	T
Polyphen		0.99	D
Vest4		0.34
MVP		0.34
MPC		0.42
ClinPred		0.028	T
GERP RS		0.23
Varity_R		0.024
gMVP		0.042
Mutation Taster		=97/3	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: rs61735823; hg19: chr21-47754549; COSMIC: COSV64026769;