chr4-157143853-CGG-GATGATGGGGGT

Position:

• chr4-157143853-CGG-GATGATGGGGGT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_000824.5(GLRB):​c.798_800delinsGATGATGGGGGT​(p.Gly267delinsMetMetGlyVal) variant causes a protein altering 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRB NM_000824.5 protein_altering
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRB	NM_000824.5	c.798_800delinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	protein_altering_variant	8/10	ENST00000264428.9	NP_000815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRB	ENST00000264428.9	c.798_800delinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	protein_altering_variant	8/10	1	NM_000824.5	ENSP00000264428	P1
GLRB	ENST00000509282.1	c.798_800delinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	protein_altering_variant	8/10	1		ENSP00000427186	P1
GLRB	ENST00000541722.5	c.798_800delinsGATGATGGGGGT	p.Gly267delinsMetMetGlyVal	protein_altering_variant	8/9	5		ENSP00000441873
GLRB	ENST00000512619.5	c.123-26579_123-26577delinsGATGATGGGGGT		intron_variant		3		ENSP00000425433

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. This variant has not been reported in the literature in individuals with GLRB-related disease. This variant is not present in population databases (ExAC no frequency). This variant, c.798_800delinsGATGATGGGGGT, is a complex sequence change that results in the deletion of 1 amino acid and the insertion of 4 amino acids in the GLRB protein (p.Gly267delinsMetMetGlyVal). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553998291; hg19: chr4-158065005;