22-20859079-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004782.4(SNAP29):c.-32C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,548,512 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: SNAP29 NM_004782.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.310

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-20859079-C-G is Benign according to our data. Variant chr22-20859079-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 340825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00655 (997/152292) while in subpopulation AFR AF= 0.0228 (946/41570). AF 95% confidence interval is 0.0216. There are 14 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP29	NM_004782.4	c.-32C>G		5_prime_UTR_variant	1/5	ENST00000215730.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP29	ENST00000215730.12	c.-32C>G		5_prime_UTR_variant	1/5	1	NM_004782.4	P1
PI4KA	ENST00000449120.1	c.-19+44G>C		intron_variant		4
SNAP29	ENST00000490458.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00656 AC: 998 AN: 152176 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00161 AC: 341 AN: 212376 Hom.: 5 AF XY: 0.00118 AC XY: 138 AN XY: 116944

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.000994

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000941

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000437

Gnomad OTH exome AF: 0.000380

GnomAD4 exome AF: 0.000659 AC: 920 AN: 1396220 Hom.: 11 Cov.: 23 AF XY: 0.000592 AC XY: 412 AN XY: 696198

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.000906

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000104

Gnomad4 OTH exome AF: 0.000946

GnomAD4 genome AF: 0.00655 AC: 997 AN: 152292 Hom.: 14 Cov.: 32 AF XY: 0.00632 AC XY: 471 AN XY: 74482

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.00734

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CEDNIK syndrome Benign:1

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	6.1
Dann	Benign	0.50
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs202138036; hg19: chr22-21213367;