X-47572946-C-T

Variant names:

• chrX-47572946-C-T
• NM_006950.3:c.2036G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_006950.3(SYN1):​c.2036G>A​(p.Arg679Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

Genes affected

SYN1 (HGNC:11494): (synapsin I) This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

SYN1 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, G2P
• intellectual disability, X-linked 50

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2305114).
• BP6: Variant X-47572946-C-T is Benign according to our data. Variant chrX-47572946-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3451834.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006950.3. 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
	SYN1	NM_006950.3	MANE Select	c.2036G>A	p.Arg679Lys	missense	Exon 13 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1998G>A	p.Gln666Gln	synonymous	Exon 13 of 13	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.2036G>A	p.Arg679Lys	missense	Exon 13 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1998G>A	p.Gln666Gln	synonymous	Exon 13 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.2033G>A	p.Arg678Lys	missense	Exon 13 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.048
Sift	Benign	0.068	T
Sift4G	Benign	0.12	T
Polyphen		0.63	P
Vest4		0.28
MutPred		0.26		Gain of ubiquitination at R679 (P = 0.0051)
MVP		0.59
MPC		1.8
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.66
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

hg19: chrX-47432345;