21-46418198-T-TATCTG

Variant names:

• chr21-46418198-T-TATCTG
• rs59957960
• NM_006031.6:c.6922-5_6922-4insTCTGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006031.6(PCNT):​c.6922-5_6922-4insTCTGA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,538,784 control chromosomes in the GnomAD database, including 10,658 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4328 hom., cov: 30)
  • Exomes 𝑓: 0.075 (6330 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.703
• Publications: 3 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 21-46418198-T-TATCTG is Benign according to our data. Variant chr21-46418198-T-TATCTG is described in ClinVar as Benign. ClinVar VariationId is 159645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 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.6922-5_6922-4insTCTGA		splice_region intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.6568-5_6568-4insTCTGA		splice_region intron	N/A	NP_001302458.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.6922-6_6922-5insATCTG		splice_region intron	N/A	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.6568-6_6568-5insATCTG		splice_region intron	N/A	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.6955-6_6955-5insATCTG		splice_region intron	N/A	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26747 AN: 151932 Hom.: 4323 Cov.: 30

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0920

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.0910 AC: 22642 AN: 248744 AF XY: 0.0862

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.0825

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0707

Gnomad OTH exome AF: 0.0771

GnomAD4 exome AF: 0.0754 AC: 104535 AN: 1386734 Hom.: 6330 Cov.: 25 AF XY: 0.0754 AC XY: 52372 AN XY: 694712

African (AFR) AF: 0.434 AC: 13136 AN: 30262

American (AMR) AF: 0.0583 AC: 2595 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.0814 AC: 2080 AN: 25544

East Asian (EAS) AF: 0.00160 AC: 63 AN: 39432

South Asian (SAS) AF: 0.0821 AC: 6938 AN: 84512

European-Finnish (FIN) AF: 0.103 AC: 5467 AN: 53304

Middle Eastern (MID) AF: 0.0712 AC: 402 AN: 5648

European-Non Finnish (NFE) AF: 0.0656 AC: 68572 AN: 1045944

Other (OTH) AF: 0.0917 AC: 5282 AN: 57598

GnomAD4 genome AF: 0.176 AC: 26785 AN: 152050 Hom.: 4328 Cov.: 30 AF XY: 0.173 AC XY: 12856 AN XY: 74360

African (AFR) AF: 0.432 AC: 17866 AN: 41344

American (AMR) AF: 0.0937 AC: 1433 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3470

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5188

South Asian (SAS) AF: 0.0919 AC: 444 AN: 4832

European-Finnish (FIN) AF: 0.106 AC: 1130 AN: 10612

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0762 AC: 5181 AN: 67992

Other (OTH) AF: 0.166 AC: 350 AN: 2112

Alfa AF: 0.0692 Hom.: 139

Asia WGS AF: 0.104 AC: 361 AN: 3478

EpiCase AF: 0.0695

EpiControl AF: 0.0678

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.70
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs59957960; hg19: chr21-47838112;