rs10517662

Variant names:

• chr4-157171909-C-T
• rs10517662
• NM_000824.5:c.*1181C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000824.5(GLRB):​c.*1181C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 151,778 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.076 (590 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GLRB NM_000824.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.770
• Publications: 7 publications found

Genes affected

GLRB (HGNC:4329): (glycine receptor beta) This gene encodes the beta subunit of the glycine receptor, which is a pentamer composed of alpha and beta subunits. The receptor functions as a neurotransmitter-gated ion channel, which produces hyperpolarization via increased chloride conductance due to the binding of glycine to the receptor. Mutations in this gene cause startle disease, also known as hereditary hyperekplexia or congenital stiff-person syndrome, a disease characterized by muscular rigidity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

GLRB Gene-Disease associations (from GenCC):

• hyperekplexia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRB	NM_000824.5	c.*1181C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000264428.9	NP_000815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRB	ENST00000264428.9	c.*1181C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_000824.5	ENSP00000264428.4
GLRB	ENST00000541722.5	c.*1470C>T		3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000441873.1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11562 AN: 151660 Hom.: 592 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0402

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0812

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0763 AC: 11575 AN: 151778 Hom.: 590 Cov.: 32 AF XY: 0.0769 AC XY: 5700 AN XY: 74164

African (AFR) AF: 0.140 AC: 5815 AN: 41498

American (AMR) AF: 0.0402 AC: 612 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3464

East Asian (EAS) AF: 0.0358 AC: 185 AN: 5166

South Asian (SAS) AF: 0.103 AC: 497 AN: 4822

European-Finnish (FIN) AF: 0.0517 AC: 546 AN: 10558

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0463 AC: 3136 AN: 67730

Other (OTH) AF: 0.0803 AC: 169 AN: 2104

Alfa AF: 0.0564 Hom.: 409

Bravo AF: 0.0778

Asia WGS AF: 0.0730 AC: 254 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.6
DANN	Benign	0.76
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10517662; hg19: chr4-158093061;