22-42876164-C-T

Variant names:

• chr22-42876164-C-T
• rs2146629763
• NM_001184970.3:c.1321G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001184970.3(PACSIN2):​c.1321G>A​(p.Glu441Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PACSIN2 NM_001184970.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

PACSIN2 (HGNC:8571): (protein kinase C and casein kinase substrate in neurons 2) This gene is a member of the protein kinase C and casein kinase substrate in neurons family. The encoded protein is involved in linking the actin cytoskeleton with vesicle formation by regulating tubulin polymerization. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184970.3. 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
	PACSIN2	NM_001184970.3	MANE Select	c.1321G>A	p.Glu441Lys	missense	Exon 10 of 11	NP_001171899.1	Q9UNF0-1
	PACSIN2	NM_001349969.2		c.1327G>A	p.Glu443Lys	missense	Exon 11 of 12	NP_001336898.1
	PACSIN2	NM_001349970.2		c.1327G>A	p.Glu443Lys	missense	Exon 11 of 12	NP_001336899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACSIN2	ENST00000263246.8	TSL:1 MANE Select	c.1321G>A	p.Glu441Lys	missense	Exon 10 of 11	ENSP00000263246.3	Q9UNF0-1
	PACSIN2	ENST00000403744.7	TSL:1	c.1321G>A	p.Glu441Lys	missense	Exon 10 of 11	ENSP00000385372.3	Q9UNF0-1
	PACSIN2	ENST00000407585.5	TSL:1	c.1198G>A	p.Glu400Lys	missense	Exon 9 of 10	ENSP00000385952.1	Q9UNF0-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111912

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

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.86	L
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.11	B
Vest4		0.92
MutPred		0.59		Gain of ubiquitination at E441 (P = 0.0085)
MVP		0.68
MPC		1.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.88
gMVP		0.79
Mutation Taster		=13/87	disease causing

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: rs2146629763; hg19: chr22-43272170;