rs116644127

Variant names:

• chr22-20859240-T-C
• rs116644127
• NM_004782.4:c.130T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-20859240-T-C
• chr22-20859240-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004782.4(SNAP29):​c.130T>C​(p.Tyr44His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,607,296 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y44C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0074 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (15 hom.)
• Consequence: SNAP29 NM_004782.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.766
• Publications: 0 publications found

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]

PI4KA Gene-Disease associations (from GenCC):

• polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057190657).
• BP6: Variant 22-20859240-T-C is Benign according to our data. Variant chr22-20859240-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 340831.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 = 0.00738 (1123/152252) while in subpopulation AFR AF = 0.0247 (1028/41556). AF 95% confidence interval is 0.0235. There are 17 homozygotes in GnomAd4. There are 550 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004782.4. 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
	SNAP29	NM_004782.4	MANE Select	c.130T>C	p.Tyr44His	missense	Exon 1 of 5	NP_004773.1	O95721

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAP29	ENST00000215730.12	TSL:1 MANE Select	c.130T>C	p.Tyr44His	missense	Exon 1 of 5	ENSP00000215730.6	O95721
	SNAP29	ENST00000880968.1		c.130T>C	p.Tyr44His	missense	Exon 1 of 5	ENSP00000551027.1
	SNAP29	ENST00000880966.1		c.130T>C	p.Tyr44His	missense	Exon 2 of 6	ENSP00000551025.1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152134 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00196 AC: 442 AN: 225234 AF XY: 0.00143

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.000646

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000939 AC: 1366 AN: 1455044 Hom.: 15 Cov.: 32 AF XY: 0.000798 AC XY: 577 AN XY: 723492

African (AFR) AF: 0.0280 AC: 938 AN: 33446

American (AMR) AF: 0.00168 AC: 73 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.000465 AC: 12 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51676

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1109862

Other (OTH) AF: 0.00167 AC: 100 AN: 60048

GnomAD4 genome AF: 0.00738 AC: 1123 AN: 152252 Hom.: 17 Cov.: 32 AF XY: 0.00739 AC XY: 550 AN XY: 74450

African (AFR) AF: 0.0247 AC: 1028 AN: 41556

American (AMR) AF: 0.00412 AC: 63 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67990

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.000607 Hom.: 0

Bravo AF: 0.00851

ESP6500AA AF: 0.0208 AC: 88

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00224 AC: 269

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	CEDNIK syndrome (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.77
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.11
Sift	Benign	0.39	T
Sift4G	Benign	0.20	T
Polyphen		0.80	P
Vest4		0.32
MVP		0.60
MPC		0.18
ClinPred		0.017	T
GERP RS		3.3
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.088
gMVP		0.38
Mutation Taster		=85/15	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: rs116644127; hg19: chr22-21213528; COSMIC: COSV99072322; COSMIC: COSV99072322;