rs17035648

Variant names:

• chr4-157097028-A-G
• rs17035648
• NM_000824.5:c.122+18882A>G

Variant summary

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

The NM_000824.5(GLRB):​c.122+18882A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,214 control chromosomes in the GnomAD database, including 1,643 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 0.14 (1643 hom., cov: 32)
• Consequence: GLRB NM_000824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRB	NM_000824.5	c.122+18882A>G		intron_variant	Intron 2 of 9	ENST00000264428.9	NP_000815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRB	ENST00000264428.9	c.122+18882A>G		intron_variant	Intron 2 of 9	1	NM_000824.5	ENSP00000264428.4

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21291 AN: 152096 Hom.: 1641 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.140 AC: 21293 AN: 152214 Hom.: 1643 Cov.: 32 AF XY: 0.143 AC XY: 10653 AN XY: 74428

African (AFR) AF: 0.119 AC: 4936 AN: 41518

American (AMR) AF: 0.144 AC: 2196 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 522 AN: 3470

East Asian (EAS) AF: 0.282 AC: 1462 AN: 5176

South Asian (SAS) AF: 0.271 AC: 1308 AN: 4826

European-Finnish (FIN) AF: 0.115 AC: 1215 AN: 10610

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9100 AN: 68004

Other (OTH) AF: 0.148 AC: 312 AN: 2112

Alfa AF: 0.144 Hom.: 3121

Bravo AF: 0.141

Asia WGS AF: 0.250 AC: 866 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.70
DANN	Benign	0.50
PhyloP100		-0.31
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: rs17035648; hg19: chr4-158018180;