22-20859128-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004782.4(SNAP29):c.18A>G(p.Lys6=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,603,778 control chromosomes in the GnomAD database, including 234,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17136 hom., cov: 33)
  • Exomes 𝑓: 0.54 (216987 hom.)
• Consequence: SNAP29 NM_004782.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.259

Genes affected

SNAP29 (HGNC:11133): (synaptosome associated protein 29) This gene, a member of the SNAP25 gene family, encodes a protein involved in multiple membrane trafficking steps. Two other members of this gene family, SNAP23 and SNAP25, encode proteins that bind a syntaxin protein and mediate synaptic vesicle membrane docking and fusion to the plasma membrane. The protein encoded by this gene binds tightly to multiple syntaxins and is localized to intracellular membrane structures rather than to the plasma membrane. While the protein is mostly membrane-bound, a significant fraction of it is found free in the cytoplasm. Use of multiple polyadenylation sites has been noted for this gene. [provided by RefSeq, Jul 2008]

PI4KA (HGNC:8983): (phosphatidylinositol 4-kinase alpha) This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-20859128-A-G is Benign according to our data. Variant chr22-20859128-A-G is described in ClinVar as [Benign]. Clinvar id is 340830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20859128-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.259 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP29	NM_004782.4	c.18A>G	p.Lys6=	synonymous_variant	1/5	ENST00000215730.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP29	ENST00000215730.12	c.18A>G	p.Lys6=	synonymous_variant	1/5	1	NM_004782.4	P1
PI4KA	ENST00000449120.1	c.-24T>C		5_prime_UTR_variant	1/4	4
SNAP29	ENST00000490458.1	n.48A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67941 AN: 151936 Hom.: 17137 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.515 AC: 116905 AN: 227086 Hom.: 31818 AF XY: 0.527 AC XY: 65509 AN XY: 124392

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.410

Gnomad SAS exome AF: 0.600

Gnomad FIN exome AF: 0.709

Gnomad NFE exome AF: 0.551

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.541 AC: 785671 AN: 1451724 Hom.: 216987 Cov.: 35 AF XY: 0.544 AC XY: 392734 AN XY: 721802

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.411

Gnomad4 ASJ exome AF: 0.507

Gnomad4 EAS exome AF: 0.442

Gnomad4 SAS exome AF: 0.603

Gnomad4 FIN exome AF: 0.702

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.525

GnomAD4 genome AF: 0.447 AC: 67958 AN: 152054 Hom.: 17136 Cov.: 33 AF XY: 0.455 AC XY: 33835 AN XY: 74342

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.712

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.438

Alfa AF: 0.503 Hom.: 13879

Bravo AF: 0.414

Asia WGS AF: 0.483 AC: 1680 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CEDNIK syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, flagged submission

clinical testing

GeneDx

Jul 06, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.0
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs1061064; hg19: chr22-21213416; COSMIC: COSV53141857; COSMIC: COSV53141857;