Variant 20-1305823-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001318234.2(SNPH):c.1386G>C(p.Lys462Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000916 in 1,418,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

SNPH
NM_001318234.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Variant links:

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]

SNPH links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18759456).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNPH	NM_001318234.2 linkuse as main transcript	c.1386G>C	p.Lys462Asn	missense_variant	7/7	ENST00000381867.6	NP_001305163.1	O15079-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SNPH	ENST00000381867.6 linkuse as main transcript	c.1386G>C	p.Lys462Asn	missense_variant	7/7	1	NM_001318234.2	ENSP00000371291.1	O15079-2
SNPH	ENST00000614659.1 linkuse as main transcript	c.1386G>C	p.Lys462Asn	missense_variant	4/4	1		ENSP00000479696.1	O15079-2
SNPH	ENST00000381873.7 linkuse as main transcript	c.1254G>C	p.Lys418Asn	missense_variant	6/6	1		ENSP00000371297.3	O15079-1
SNPH	ENST00000649598.1 linkuse as main transcript	c.1353G>C	p.Lys451Asn	missense_variant	6/6			ENSP00000496966.1	A0A3B3IRY9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000916

AC:

AN:

1418658

Hom.:

Cov.:

AF XY:

0.00000997

AC XY:

AN XY:

702424

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.1254G>C (p.K418N) alteration is located in exon 6 (coding exon 4) of the SNPH gene. This alteration results from a G to C substitution at nucleotide position 1254, causing the lysine (K) at amino acid position 418 to be replaced by an asparagine (N). 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

0.58

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

T;T;.;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.9

.;L;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

.;N;N;.

REVEL

Benign

0.071

Sift

Uncertain

0.0070

.;D;D;.

Sift4G

Uncertain

0.014

.;D;D;D

Polyphen

0.83, 0.90

.;P;P;P

Vest4

0.37, 0.40

MutPred

0.33

.;Loss of methylation at K418 (P = 0.007);.;.;

MVP

0.16

MPC

0.86

ClinPred

0.80

GERP RS

2.3

Varity_R

0.27

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over