chr22-38071734-G-C

Position:

• chr22-38071734-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012407.4(PICK1):​c.546G>C​(p.Gln182His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PICK1 NM_012407.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PICK1	NM_012407.4	c.546G>C	p.Gln182His	missense_variant	8/13	ENST00000356976.8	NP_036539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PICK1	ENST00000356976.8	c.546G>C	p.Gln182His	missense_variant	8/13	1	NM_012407.4	ENSP00000349465.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461096 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.546G>C (p.Q182H) alteration is located in exon 8 (coding exon 7) of the PICK1 gene. This alteration results from a G to C substitution at nucleotide position 546, causing the glutamine (Q) at amino acid position 182 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.022	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.37	B;.;B
Vest4		0.70
MutPred		0.74		Loss of MoRF binding (P = 0.1554);Loss of MoRF binding (P = 0.1554);Loss of MoRF binding (P = 0.1554);
MVP		0.96
MPC		0.74
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-38467741;