Genetic Variant PICK1:p.Gly62Cys (chr22-38065032-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012407.4(PICK1):c.184G>T(p.Gly62Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G62S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PICK1
NM_012407.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.66

Publications

0 publications found

Variant links:

Genes affected

PICK1 (HGNC:9394): (protein interacting with PRKCA 1) The protein encoded by this gene contains a PDZ domain, through which it interacts with protein kinase C, alpha (PRKCA). This protein may function as an adaptor that binds to and organizes the subcellular localization of a variety of membrane proteins. It has been shown to interact with multiple glutamate receptor subtypes, monoamine plasma membrane transporters, as well as non-voltage gated sodium channels, and may target PRKCA to these membrane proteins and thus regulate their distribution and function. This protein has also been found to act as an anchoring protein that specifically targets PRKCA to mitochondria in a ligand-specific manner. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

PICK1 Gene-Disease associations (from GenCC):

male infertility due to globozoospermia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PICK1 links:

ENSG00000233739 (HGNC:):

ENSG00000233739 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012407.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PICK1	NM_012407.4	MANE Select	c.184G>T	p.Gly62Cys	missense	Exon 4 of 13	NP_036539.1	Q9NRD5-1
PICK1	NM_001039583.1		c.184G>T	p.Gly62Cys	missense	Exon 4 of 13	NP_001034672.1	Q9NRD5-1
PICK1	NM_001039584.1		c.184G>T	p.Gly62Cys	missense	Exon 4 of 13	NP_001034673.1	Q9NRD5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PICK1	ENST00000356976.8	TSL:1 MANE Select	c.184G>T	p.Gly62Cys	missense	Exon 4 of 13	ENSP00000349465.3	Q9NRD5-1
PICK1	ENST00000951428.1		c.184G>T	p.Gly62Cys	missense	Exon 4 of 14	ENSP00000621487.1
PICK1	ENST00000951430.1		c.184G>T	p.Gly62Cys	missense	Exon 4 of 14	ENSP00000621489.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

4.3

PhyloP100

9.7

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.97

MutPred

0.86

Loss of disorder (P = 0.0578)

MVP

0.82

MPC

1.9

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.92

Mutation Taster

=4/96

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over