rs587784310

Variant names:

• chr21-46326372-C-T
• rs587784310
• NM_001414902.1:c.85C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-46326372-C-T
• chr21-46326372-C-G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001414902.1(LOC128092249):​c.85C>T​(p.Arg29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 6/8 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. R29L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LOC128092249 NM_001414902.1 missense
• Scores: Splicing: ADA: 0.001824
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.70
• Publications: 0 publications found

Genes affected

LOC128092249 (HGNC:0):

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 21-46326372-C-T is Benign according to our data. Variant chr21-46326372-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159620.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414902.1. 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
	LOC128092249	NM_001414902.1	MANE Select	c.85C>T	p.Arg29Cys	missense	Exon 1 of 1	NP_001401831.1	A0A494C0I6
	PCNT	NM_006031.6	MANE Select	c.55-5C>T		splice_region intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.-300-5C>T		splice_region intron	N/A	NP_001302458.1	O95613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000286224	ENST00000652508.1	MANE Select	c.85C>T	p.Arg29Cys	missense	Exon 1 of 1	ENSP00000498568.1	A0A494C0I6
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.55-5C>T		splice_region intron	N/A	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.-300-5C>T		splice_region intron	N/A	ENSP00000511989.1	O95613-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Benign	0.88
PhyloP100		2.7
PromoterAI		-0.039	Neutral
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.0060
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: rs587784310; hg19: chr21-47746286; COSMIC: COSV99388196; COSMIC: COSV99388196;