NM_006950.3:c.1967C>T

Variant names:

• chrX-47574017-G-A
• rs1391622247
• NM_006950.3:c.1967C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006950.3(SYN1):​c.1967C>T​(p.Pro656Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,146,013 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P656S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000029 (0 hom. 1 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.81
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21159509).

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.1967C>T	p.Pro656Leu	missense	Exon 12 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1967C>T	p.Pro656Leu	missense	Exon 12 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.1967C>T	p.Pro656Leu	missense	Exon 12 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1967C>T	p.Pro656Leu	missense	Exon 12 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1964C>T	p.Pro655Leu	missense	Exon 12 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112345 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000290 AC: 3 AN: 1033668 Hom.: 0 Cov.: 32 AF XY: 0.00000301 AC XY: 1 AN XY: 332442

African (AFR) AF: 0.00 AC: 0 AN: 24140

American (AMR) AF: 0.00 AC: 0 AN: 26757

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17947

East Asian (EAS) AF: 0.00 AC: 0 AN: 26330

South Asian (SAS) AF: 0.00 AC: 0 AN: 48434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2836

European-Non Finnish (NFE) AF: 0.00000368 AC: 3 AN: 815138

Other (OTH) AF: 0.00 AC: 0 AN: 43708

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112345 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34561

African (AFR) AF: 0.00 AC: 0 AN: 30943

American (AMR) AF: 0.00 AC: 0 AN: 10823

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6211

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53007

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.030	B
Vest4		0.34
MutPred		0.30		Loss of catalytic residue at P655 (P = 0.0165)
MVP		0.62
MPC		2.7
ClinPred		0.92	D
GERP RS		3.8
Varity_R		0.24
gMVP		0.40
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: rs1391622247; hg19: chrX-47433416;