17-11241631-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207386.4(SHISA6):c.209C>T(p.Ala70Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,346,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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. A70S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

SHISA6
NM_207386.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.173

Variant links:

Genes affected

SHISA6 (HGNC:34491): (shisa family member 6) Predicted to enable ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including excitatory chemical synaptic transmission; regulation of short-term neuronal synaptic plasticity; and regulation of signal transduction. Predicted to be located in asymmetric, glutamatergic, excitatory synapse. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in glutamatergic synapse; postsynaptic density; and synaptic membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHISA6 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08107805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHISA6	NM_207386.4 linkuse as main transcript	c.209C>T	p.Ala70Val	missense_variant	1/6	ENST00000441885.8
SHISA6	NM_001173462.2 linkuse as main transcript	c.209C>T	p.Ala70Val	missense_variant	1/5
SHISA6	NM_001173461.2 linkuse as main transcript	c.209C>T	p.Ala70Val	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHISA6	ENST00000441885.8 linkuse as main transcript	c.209C>T	p.Ala70Val	missense_variant	1/6	5	NM_207386.4		Q6ZSJ9-3
SHISA6	ENST00000432116.7 linkuse as main transcript	c.209C>T	p.Ala70Val	missense_variant	1/5	1			Q6ZSJ9-2
SHISA6	ENST00000409168.7 linkuse as main transcript	c.209C>T	p.Ala70Val	missense_variant	1/4	1		P1	Q6ZSJ9-1
	ENST00000648331.1 linkuse as main transcript	n.98+334G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150240

Hom.:

Cov.:

show subpopulations

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000164

AC:

AN:

12188

Hom.:

AF XY:

0.000145

AC XY:

AN XY:

6904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000279

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000259

AC:

AN:

1195924

Hom.:

Cov.:

AF XY:

0.0000310

AC XY:

AN XY:

580240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000361

Gnomad4 SAS exome

AF:

0.0000219

Gnomad4 FIN exome

AF:

0.0000732

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73272

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000834

AC:

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

Jan 30, 2024

The c.209C>T (p.A70V) alteration is located in exon 1 (coding exon 1) of the SHISA6 gene. This alteration results from a C to T substitution at nucleotide position 209, causing the alanine (A) at amino acid position 70 to be replaced by a valine (V). 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

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.66

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.61

T;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.081

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.067

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0090

B;.;B

Vest4

0.075

MutPred

0.17

Gain of MoRF binding (P = 0.1117);Gain of MoRF binding (P = 0.1117);Gain of MoRF binding (P = 0.1117);

MVP

0.030

ClinPred

0.059

GERP RS

2.6

Varity_R

0.059

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