17-11241610-G-C

Position:

• chr17-11241610-G-C

Variant summary

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

The NM_207386.4(SHISA6):​c.188G>C​(p.Arg63Pro) 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. 13/19 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: SHISA6 NM_207386.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.127

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]

ENSG00000285541 (HGNC:):

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=0.12565205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHISA6	NM_207386.4	c.188G>C	p.Arg63Pro	missense_variant	1/6	ENST00000441885.8	NP_997269.2
SHISA6	NM_001173462.2	c.188G>C	p.Arg63Pro	missense_variant	1/5		NP_001166933.1
SHISA6	NM_001173461.2	c.188G>C	p.Arg63Pro	missense_variant	1/4		NP_001166932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHISA6	ENST00000441885.8	c.188G>C	p.Arg63Pro	missense_variant	1/6	5	NM_207386.4	ENSP00000390084.3
SHISA6	ENST00000432116.7	c.188G>C	p.Arg63Pro	missense_variant	1/5	1		ENSP00000388659.3
SHISA6	ENST00000409168.7	c.188G>C	p.Arg63Pro	missense_variant	1/4	1		ENSP00000387157.3
ENSG00000285541	ENST00000648331.1	n.98+355C>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jul 23, 2024

The c.188G>C (p.R63P) alteration is located in exon 1 (coding exon 1) of the SHISA6 gene. This alteration results from a G to C substitution at nucleotide position 188, causing the arginine (R) at amino acid position 63 to be replaced by a proline (P). 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	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.0034	.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.69	P;.;B
Vest4		0.085
MutPred		0.28		Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);
MVP		0.19
ClinPred		0.12	T
GERP RS		0.52
Varity_R		0.16
gMVP		0.37

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

Other links and lift over

dbSNP: rs1386813796; hg19: chr17-11144927;