20-1305044-A-C

Position:

• chr20-1305044-A-C

Variant summary

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

The NM_001318234.2(SNPH):​c.607A>C​(p.Lys203Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNPH NM_001318234.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.06

Genes affected

SNPH (HGNC:15931): (syntaphilin) Syntaxin-1, synaptobrevin/VAMP, and SNAP25 interact to form the SNARE complex, which is required for synaptic vesicle docking and fusion. The protein encoded by this gene is membrane-associated and inhibits SNARE complex formation by binding free syntaxin-1. Expression of this gene appears to be brain-specific. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNPH	NM_001318234.2	c.607A>C	p.Lys203Gln	missense_variant	7/7	ENST00000381867.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNPH	ENST00000381867.6	c.607A>C	p.Lys203Gln	missense_variant	7/7	1	NM_001318234.2	P3
SNPH	ENST00000614659.1	c.607A>C	p.Lys203Gln	missense_variant	4/4	1		P3
SNPH	ENST00000381873.7	c.475A>C	p.Lys159Gln	missense_variant	6/6	1		A1
SNPH	ENST00000649598.1	c.574A>C	p.Lys192Gln	missense_variant	6/6			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Sep 22, 2022

The c.475A>C (p.K159Q) alteration is located in exon 6 (coding exon 4) of the SNPH gene. This alteration results from a A to C substitution at nucleotide position 475, causing the lysine (K) at amino acid position 159 to be replaced by a glutamine (Q). 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	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.1	.;M;.;.
MutationTaster	Benign	0.87	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	.;N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.038	.;D;D;.
Sift4G	Uncertain	0.038	.;D;D;D
Polyphen		0.92	.;P;P;P
Vest4		0.30, 0.27, 0.28
MutPred		0.50		.;Loss of ubiquitination at K159 (P = 0.021);.;.;
MVP		0.64
MPC		1.5
ClinPred		0.90	D
GERP RS		4.6
Varity_R		0.24
gMVP		0.31

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: chr20-1285688;