rs61735814

Variant names:

• chr21-46422075-C-T
• rs61735814
• NM_006031.6:c.7130C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-46422075-C-T
• chr21-46422075-C-A

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.7130C>T​(p.Pro2377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,866 control chromosomes in the GnomAD database, including 2,622 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2377P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (195 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2427 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.50
• Publications: 18 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=0.0017070472).
• BP6: Variant 21-46422075-C-T is Benign according to our data. Variant chr21-46422075-C-T is described in ClinVar as Benign. ClinVar VariationId is 138631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 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.7130C>T	p.Pro2377Leu	missense	Exon 32 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6776C>T	p.Pro2259Leu	missense	Exon 32 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.7130C>T	p.Pro2377Leu	missense	Exon 32 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6776C>T	p.Pro2259Leu	missense	Exon 32 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.7163C>T	p.Pro2388Leu	missense	Exon 33 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6311 AN: 152194 Hom.: 196 Cov.: 33

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0625

Gnomad OTH AF: 0.0382

GnomAD2 exomes AF: 0.0431 AC: 10807 AN: 251014 AF XY: 0.0430

Gnomad AFR exome AF: 0.00857

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0570

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0608

Gnomad OTH exome AF: 0.0464

GnomAD4 exome AF: 0.0538 AC: 78595 AN: 1461554 Hom.: 2427 Cov.: 32 AF XY: 0.0528 AC XY: 38378 AN XY: 727076

African (AFR) AF: 0.00777 AC: 260 AN: 33480

American (AMR) AF: 0.0198 AC: 884 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 1447 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0135 AC: 1168 AN: 86258

European-Finnish (FIN) AF: 0.0834 AC: 4436 AN: 53160

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5768

European-Non Finnish (NFE) AF: 0.0606 AC: 67396 AN: 1111940

Other (OTH) AF: 0.0473 AC: 2858 AN: 60390

GnomAD4 genome AF: 0.0414 AC: 6309 AN: 152312 Hom.: 195 Cov.: 33 AF XY: 0.0408 AC XY: 3042 AN XY: 74468

African (AFR) AF: 0.00979 AC: 407 AN: 41586

American (AMR) AF: 0.0261 AC: 399 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4828

European-Finnish (FIN) AF: 0.0851 AC: 903 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0625 AC: 4250 AN: 68016

Other (OTH) AF: 0.0378 AC: 80 AN: 2116

Alfa AF: 0.0501 Hom.: 391

Bravo AF: 0.0360

TwinsUK AF: 0.0537 AC: 199

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0609 AC: 524

ExAC AF: 0.0433 AC: 5263

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0541

EpiControl AF: 0.0536

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.085
DANN	Benign	0.63
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.086
Sift	Benign	0.23	T
Sift4G	Benign	0.13	T
Polyphen		0.76	P
Vest4		0.031
MPC		0.41
ClinPred		0.012	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.011
gMVP		0.094
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61735814; hg19: chr21-47841989; COSMIC: COSV64027462; COSMIC: COSV64027462;