chr22-38072497-G-C

Variant names:

• chr22-38072497-G-C
• rs201758961
• NM_012407.4:c.577G>C

Variant summary

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

The NM_012407.4(PICK1):​c.577G>C​(p.Val193Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V193M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PICK1 NM_012407.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79
• Publications: 2 publications found

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

ENSG00000233739 (HGNC:):

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_012407.4. 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
	PICK1	NM_012407.4	MANE Select	c.577G>C	p.Val193Leu	missense	Exon 9 of 13	NP_036539.1	Q9NRD5-1
	PICK1	NM_001039583.1		c.577G>C	p.Val193Leu	missense	Exon 9 of 13	NP_001034672.1	Q9NRD5-1
	PICK1	NM_001039584.1		c.577G>C	p.Val193Leu	missense	Exon 9 of 13	NP_001034673.1	Q9NRD5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PICK1	ENST00000356976.8	TSL:1 MANE Select	c.577G>C	p.Val193Leu	missense	Exon 9 of 13	ENSP00000349465.3	Q9NRD5-1
	PICK1	ENST00000951428.1		c.682G>C	p.Val228Leu	missense	Exon 10 of 14	ENSP00000621487.1
	PICK1	ENST00000951430.1		c.682G>C	p.Val228Leu	missense	Exon 10 of 14	ENSP00000621489.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250576 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461068 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726848

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.36
Sift	Benign	0.27	T
Sift4G	Benign	0.29	T
Polyphen		0.015	B
Vest4		0.77
MutPred		0.62		Loss of sheet (P = 0.0457)
MVP		0.83
MPC		0.78
ClinPred		0.82	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.83
Mutation Taster		=64/36	polymorphism

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: rs201758961; hg19: chr22-38468504;