rs1553998291

Variant names:

• chr4-157143853-CGG-GATGATGGGGGT
• rs1553998291
• NM_000824.5:c.798_800delCGGinsGATGATGGGGGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_000824.5(GLRB):​c.798_800delCGGinsGATGATGGGGGT​(p.Gly267delinsMetMetGlyVal) variant causes a missense, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V266V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRB NM_000824.5 missense, disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93
• 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, Labcorp Genetics (formerly Invitae), G2P
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000824.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	NM_000824.5	MANE Select	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense disruptive_inframe_insertion	N/A	NP_000815.1	P48167-1
	GLRB	NM_001166060.2		c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense disruptive_inframe_insertion	N/A	NP_001159532.1	P48167-1
	GLRB	NM_001440545.1		c.504_506delCGGinsGATGATGGGGGT	p.Gly169delinsMetMetGlyVal	missense disruptive_inframe_insertion	N/A	NP_001427474.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	ENST00000264428.9	TSL:1 MANE Select	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense disruptive_inframe_insertion	N/A	ENSP00000264428.4	P48167-1
	GLRB	ENST00000509282.1	TSL:1	c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense disruptive_inframe_insertion	N/A	ENSP00000427186.1	P48167-1
	GLRB	ENST00000960009.1		c.798_800delCGGinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	missense disruptive_inframe_insertion	N/A	ENSP00000630068.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperekplexia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553998291; hg19: chr4-158065005;