rs35940413

Variant names:

• chr21-46411595-A-G
• rs35940413
• NM_006031.6:c.5522A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-46411595-A-G
• chr21-46411595-A-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.5522A>G​(p.Asn1841Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,612,692 control chromosomes in the GnomAD database, including 19,522 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1841N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (5452 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14070 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.395
• Publications: 17 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=2.9724836E-4).
• BP6: Variant 21-46411595-A-G is Benign according to our data. Variant chr21-46411595-A-G is described in ClinVar as Benign. ClinVar VariationId is 95336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 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.5522A>G	p.Asn1841Ser	missense	Exon 28 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5168A>G	p.Asn1723Ser	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.5522A>G	p.Asn1841Ser	missense	Exon 28 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.5168A>G	p.Asn1723Ser	missense	Exon 28 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.5555A>G	p.Asn1852Ser	missense	Exon 29 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32584 AN: 151970 Hom.: 5447 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00582

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.133 AC: 32782 AN: 247286 AF XY: 0.128

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.00311

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.123 AC: 179693 AN: 1460598 Hom.: 14070 Cov.: 34 AF XY: 0.122 AC XY: 88755 AN XY: 726638

African (AFR) AF: 0.485 AC: 16227 AN: 33462

American (AMR) AF: 0.0904 AC: 4041 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6069 AN: 26118

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39686

South Asian (SAS) AF: 0.104 AC: 8964 AN: 86256

European-Finnish (FIN) AF: 0.112 AC: 5881 AN: 52456

Middle Eastern (MID) AF: 0.157 AC: 906 AN: 5768

European-Non Finnish (NFE) AF: 0.116 AC: 128902 AN: 1111768

Other (OTH) AF: 0.143 AC: 8628 AN: 60374

GnomAD4 genome AF: 0.214 AC: 32621 AN: 152094 Hom.: 5452 Cov.: 33 AF XY: 0.209 AC XY: 15550 AN XY: 74370

African (AFR) AF: 0.463 AC: 19232 AN: 41494

American (AMR) AF: 0.132 AC: 2015 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3470

East Asian (EAS) AF: 0.00583 AC: 30 AN: 5148

South Asian (SAS) AF: 0.111 AC: 534 AN: 4806

European-Finnish (FIN) AF: 0.112 AC: 1191 AN: 10606

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8230 AN: 67966

Other (OTH) AF: 0.215 AC: 452 AN: 2106

Alfa AF: 0.147 Hom.: 2374

Bravo AF: 0.227

TwinsUK AF: 0.106 AC: 394

ALSPAC AF: 0.105 AC: 404

ESP6500AA AF: 0.458 AC: 2018

ESP6500EA AF: 0.130 AC: 1114

ExAC AF: 0.139 AC: 16895

Asia WGS AF: 0.114 AC: 396 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.129

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.41
DANN	Benign	0.17
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.40
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.065
ClinPred		0.0043	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.074
Mutation Taster		=96/4	polymorphism (auto)

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: rs35940413; hg19: chr21-47831509; COSMIC: COSV64027443;