rs59957960

Variant names:

• chr21-46418198-T-TACCTG
• rs59957960
• NM_006031.6:c.6922-5_6922-4insCCTGA

Your query was ambiguous. Multiple possible variants found:

• chr21-46418198-T-TACCTG
• chr21-46418198-T-TATCTG
• chr21-46418198-T-TATTTG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006031.6(PCNT):​c.6922-5_6922-4insCCTGA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,391,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.703

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6	c.6922-5_6922-4insCCTGA		splice_region_variant, intron_variant	Intron 30 of 46	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6568-5_6568-4insCCTGA		splice_region_variant, intron_variant	Intron 30 of 46		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.6922-6_6922-5insACCTG		splice_region_variant, intron_variant	Intron 30 of 46	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1391560 Hom.: 0 Cov.: 25 AF XY: 0.00000574 AC XY: 4 AN XY: 696954

Gnomad4 AFR exome AF: 0.0000978

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 28, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the PCNT gene. The c.6922-5_6922-4insCCTGA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.6922-5_6922-4insCCTGA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.6922-5_6922-4insCCTGA damages or destroys the natural acceptor site in intron 30 and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59957960; hg19: chr21-47838112;