NM_000824.5:c.751+701T>A

Variant names:

• chr4-157139650-T-A
• rs6814940
• NM_000824.5:c.751+701T>A

Variant summary

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

The NM_000824.5(GLRB):​c.751+701T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0861 in 152,030 control chromosomes in the GnomAD database, including 1,536 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 0.086 (1536 hom., cov: 32)
• Consequence: GLRB NM_000824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.687
• Publications: 0 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000824.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	NM_000824.5	MANE Select	c.751+701T>A		intron	N/A	NP_000815.1
	GLRB	NM_001166060.2		c.751+701T>A		intron	N/A	NP_001159532.1
	GLRB	NM_001440545.1		c.457+701T>A		intron	N/A	NP_001427474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	ENST00000264428.9	TSL:1 MANE Select	c.751+701T>A		intron	N/A	ENSP00000264428.4
	GLRB	ENST00000509282.1	TSL:1	c.751+701T>A		intron	N/A	ENSP00000427186.1
	GLRB	ENST00000541722.5	TSL:5	c.751+701T>A		intron	N/A	ENSP00000441873.1

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13009 AN: 151914 Hom.: 1507 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0662

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0861 AC: 13084 AN: 152030 Hom.: 1536 Cov.: 32 AF XY: 0.0818 AC XY: 6081 AN XY: 74310

African (AFR) AF: 0.273 AC: 11337 AN: 41486

American (AMR) AF: 0.0457 AC: 698 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3466

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4830

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 777 AN: 67882

Other (OTH) AF: 0.0655 AC: 138 AN: 2106

Alfa AF: 0.0548 Hom.: 115

Bravo AF: 0.0994

Asia WGS AF: 0.0280 AC: 100 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		0.69
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: rs6814940; hg19: chr4-158060802;