rs1181626947

Positions:

• chr5-151822777-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_000171.4(GLRA1):​c.1246G>A​(p.Asp416Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.72

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 5-151822777-C-T is Pathogenic according to our data. Variant chr5-151822777-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545477.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.1246G>A	p.Asp416Asn	missense_variant	9/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.1270G>A	p.Asp424Asn	missense_variant	9/9
GLRA1	NM_001292000.2	c.997G>A	p.Asp333Asn	missense_variant	8/8
GLRA1	XM_047417105.1	c.1294G>A	p.Asp432Asn	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.1246G>A	p.Asp416Asn	missense_variant	9/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.1270G>A	p.Asp424Asn	missense_variant	9/9	1		A1
GLRA1	ENST00000462581.6	c.*1004G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251398 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135864

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727130

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Lab, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College

-

The p.Asp424Asn variant in the GLRA1 gene has been detected in a patient with Hyperekplexia. The variant was detected in the homozygous condition in the patient and the same was segregating from the parents. This clearly suggests the autosomal recessive mode of inheritance. The patient was responding to the clonazepam treatment. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.90		.;Gain of MoRF binding (P = 0.0544);
MVP		0.96
MPC		0.33
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.96

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: rs1181626947; hg19: chr5-151202338; COSMIC: COSV51026778;