rs62636580

Positions:

• chr5-151822799-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000171.4(GLRA1):​c.1224C>T​(p.Phe408=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,614,090 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (137 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (135 hom.)
• Consequence: GLRA1 NM_000171.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.52

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-151822799-G-A is Benign according to our data. Variant chr5-151822799-G-A is described in ClinVar as [Benign]. Clinvar id is 352306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRA1	NM_000171.4	c.1224C>T	p.Phe408=	synonymous_variant	9/9	ENST00000274576.9
GLRA1	NM_001146040.2	c.1248C>T	p.Phe416=	synonymous_variant	9/9
GLRA1	NM_001292000.2	c.975C>T	p.Phe325=	synonymous_variant	8/8
GLRA1	XM_047417105.1	c.1272C>T	p.Phe424=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRA1	ENST00000274576.9	c.1224C>T	p.Phe408=	synonymous_variant	9/9	1	NM_000171.4	P4
GLRA1	ENST00000455880.2	c.1248C>T	p.Phe416=	synonymous_variant	9/9	1		A1
GLRA1	ENST00000462581.6	c.*982C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3536 AN: 152152 Hom.: 135 Cov.: 31

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00590 AC: 1484 AN: 251412 Hom.: 56 AF XY: 0.00411 AC XY: 558 AN XY: 135876

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00243 AC: 3548 AN: 1461820 Hom.: 135 Cov.: 31 AF XY: 0.00209 AC XY: 1519 AN XY: 727218

Gnomad4 AFR exome AF: 0.0855

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.0233 AC: 3554 AN: 152270 Hom.: 137 Cov.: 31 AF XY: 0.0222 AC XY: 1655 AN XY: 74458

Gnomad4 AFR AF: 0.0810

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0129 Hom.: 47

Bravo AF: 0.0269

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

Hereditary hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.73

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: rs62636580; hg19: chr5-151202360;