chr21-46324213-G-T

Variant names:

• chr21-46324213-G-T
• rs138595914
• NM_006031.6:c.-16G>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.-16G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,606,990 control chromosomes in the GnomAD database, including 2,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (211 hom., cov: 35)
  • Exomes 𝑓: 0.057 (2662 hom.)
• Consequence: PCNT NM_006031.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.135
• Publications: 8 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]

C21orf58 (HGNC:1300): (chromosome 21 open reading frame 58)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 21-46324213-G-T is Benign according to our data. Variant chr21-46324213-G-T is described in ClinVar as Benign. ClinVar VariationId is 138617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0645 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.-16G>T		5_prime_UTR	Exon 1 of 47	NP_006022.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.-16G>T		5_prime_UTR	Exon 1 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000695558.1		c.-16G>T		5_prime_UTR	Exon 1 of 48	ENSP00000512015.1	A0A8Q3SHZ3
	PCNT	ENST00000695526.1		c.-16G>T		5_prime_UTR	Exon 1 of 15	ENSP00000511988.1	A0A8Q3SHV6

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6577 AN: 152176 Hom.: 212 Cov.: 35

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0440 AC: 10480 AN: 238208 AF XY: 0.0439

Gnomad AFR exome AF: 0.00810

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0636

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0568 AC: 82568 AN: 1454696 Hom.: 2662 Cov.: 31 AF XY: 0.0557 AC XY: 40258 AN XY: 723282

African (AFR) AF: 0.00824 AC: 275 AN: 33386

American (AMR) AF: 0.0203 AC: 892 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1430 AN: 25918

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39534

South Asian (SAS) AF: 0.0135 AC: 1149 AN: 85304

European-Finnish (FIN) AF: 0.0853 AC: 4497 AN: 52718

Middle Eastern (MID) AF: 0.0249 AC: 143 AN: 5746

European-Non Finnish (NFE) AF: 0.0642 AC: 71174 AN: 1108022

Other (OTH) AF: 0.0500 AC: 3005 AN: 60056

GnomAD4 genome AF: 0.0432 AC: 6575 AN: 152294 Hom.: 211 Cov.: 35 AF XY: 0.0423 AC XY: 3152 AN XY: 74466

African (AFR) AF: 0.0101 AC: 419 AN: 41576

American (AMR) AF: 0.0262 AC: 401 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3470

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

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0858 AC: 910 AN: 10612

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0661 AC: 4493 AN: 68008

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0356 Hom.: 47

Bravo AF: 0.0375

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.2
DANN	Benign	0.60
PhyloP100		-0.14
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=296/4	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: rs138595914; hg19: chr21-47744127; COSMIC: COSV52449400; COSMIC: COSV52449400;