rs121918417
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000171.4(GLRA1):c.777C>G(p.Ser259Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
GLRA1
NM_000171.4 missense
NM_000171.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 1.63
Genes affected
GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a helix (size 11) in uniprot entity GLRA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000171.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 5-151851525-G-C is Pathogenic according to our data. Variant chr5-151851525-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16071.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-151851525-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.777C>G | p.Ser259Arg | missense_variant | 7/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.777C>G | p.Ser259Arg | missense_variant | 7/9 | ||
GLRA1 | NM_001292000.2 | c.528C>G | p.Ser176Arg | missense_variant | 6/8 | ||
GLRA1 | XM_047417105.1 | c.825C>G | p.Ser275Arg | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.777C>G | p.Ser259Arg | missense_variant | 7/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.777C>G | p.Ser259Arg | missense_variant | 7/9 | 1 | A1 | ||
GLRA1 | ENST00000471351.2 | n.1060C>G | non_coding_transcript_exon_variant | 7/8 | 1 | ||||
GLRA1 | ENST00000462581.6 | c.*535C>G | 3_prime_UTR_variant, NMD_transcript_variant | 6/8 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Hyperekplexia 1 Pathogenic:2
Pathogenic, no assertion criteria provided | curation | GeneReviews | Oct 04, 2012 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0635);Gain of MoRF binding (P = 0.0635);
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at