1-109476943-A-C

Position:

• chr1-109476943-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040709.2(SYPL2):​c.422A>C​(p.Asn141Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYPL2 NM_001040709.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

Genes affected

SYPL2 (HGNC:27638): (synaptophysin like 2) Involved in substantia nigra development. Predicted to be integral component of membrane. Predicted to be active in synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23093927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYPL2	NM_001040709.2	c.422A>C	p.Asn141Thr	missense_variant	4/6	ENST00000369872.4	NP_001035799.1
SYPL2	XM_011541283.3	c.422A>C	p.Asn141Thr	missense_variant	4/7		XP_011539585.1
SYPL2	XM_011541284.3	c.422A>C	p.Asn141Thr	missense_variant	4/6		XP_011539586.1
SYPL2	XM_011541285.2	c.422A>C	p.Asn141Thr	missense_variant	4/5		XP_011539587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYPL2	ENST00000369872.4	c.422A>C	p.Asn141Thr	missense_variant	4/6	1	NM_001040709.2	ENSP00000358888.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.422A>C (p.N141T) alteration is located in exon 4 (coding exon 4) of the SYPL2 gene. This alteration results from a A to C substitution at nucleotide position 422, causing the asparagine (N) at amino acid position 141 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.056
Sift	Uncertain	0.028	D
Sift4G	Benign	0.11	T
Polyphen		0.0070	B
Vest4		0.40
MutPred		0.61		Loss of catalytic residue at N141 (P = 0.0806);
MVP		0.076
MPC		0.19
ClinPred		0.41	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-110019565;