Genetic Variant PICK1:p.Leu14Leu (chr22-38059234-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_012407.4(PICK1):c.42C>G(p.Leu14Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PICK1
NM_012407.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00003708

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.52

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_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP7

Synonymous conserved (PhyloP=-2.53 with no splicing effect.

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.42C>G	p.Leu14Leu	splice_region synonymous	Exon 3 of 13	NP_036539.1	Q9NRD5-1
PICK1	NM_001039583.1		c.42C>G	p.Leu14Leu	splice_region synonymous	Exon 3 of 13	NP_001034672.1	Q9NRD5-1
PICK1	NM_001039584.1		c.42C>G	p.Leu14Leu	splice_region synonymous	Exon 3 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.42C>G	p.Leu14Leu	splice_region synonymous	Exon 3 of 13	ENSP00000349465.3	Q9NRD5-1
PICK1	ENST00000951428.1		c.42C>G	p.Leu14Leu	splice_region synonymous	Exon 3 of 14	ENSP00000621487.1
PICK1	ENST00000951430.1		c.42C>G	p.Leu14Leu	splice_region synonymous	Exon 3 of 14	ENSP00000621489.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418692

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32346

American (AMR)

AF:

0.00

AC:

AN:

38814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25410

East Asian (EAS)

AF:

0.00

AC:

AN:

37234

South Asian (SAS)

AF:

0.00

AC:

AN:

80560

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1088998

Other (OTH)

AF:

0.00

AC:

AN:

58760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.090

(source)

DANN

Benign

0.76

PhyloP100

-2.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.094

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