22-38074931-C-T

Variant names:

• chr22-38074931-C-T
• rs149474436
• NM_012407.4:c.1047C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012407.4(PICK1):​c.1047C>T​(p.Tyr349Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,662 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (55 hom.)
• Consequence: PICK1 NM_012407.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0320
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 22-38074931-C-T is Benign according to our data. Variant chr22-38074931-C-T is described in ClinVar as Benign. ClinVar VariationId is 712400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.032 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00217 (330/152368) while in subpopulation EAS AF = 0.037 (192/5184). AF 95% confidence interval is 0.0328. There are 7 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1047C>T	p.Tyr349Tyr	synonymous	Exon 13 of 13	NP_036539.1	Q9NRD5-1
	PICK1	NM_001039583.1		c.1047C>T	p.Tyr349Tyr	synonymous	Exon 13 of 13	NP_001034672.1	Q9NRD5-1
	PICK1	NM_001039584.1		c.1047C>T	p.Tyr349Tyr	synonymous	Exon 13 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.1047C>T	p.Tyr349Tyr	synonymous	Exon 13 of 13	ENSP00000349465.3	Q9NRD5-1
	PICK1	ENST00000951428.1		c.1152C>T	p.Tyr384Tyr	synonymous	Exon 14 of 14	ENSP00000621487.1
	PICK1	ENST00000951430.1		c.1152C>T	p.Tyr384Tyr	synonymous	Exon 14 of 14	ENSP00000621489.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152250 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00505 AC: 1265 AN: 250606 AF XY: 0.00581

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00199 AC: 2901 AN: 1461294 Hom.: 55 Cov.: 32 AF XY: 0.00248 AC XY: 1804 AN XY: 726922

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0290 AC: 1151 AN: 39700

South Asian (SAS) AF: 0.0167 AC: 1438 AN: 86256

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52874

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111974

Other (OTH) AF: 0.00401 AC: 242 AN: 60384

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152368 Hom.: 7 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74504

African (AFR) AF: 0.000962 AC: 40 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0370 AC: 192 AN: 5184

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4832

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: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.00223

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.6
DANN	Benign	0.89
PhyloP100		0.032
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149474436; hg19: chr22-38470938; COSMIC: COSV57635331; COSMIC: COSV57635331;