4-157076225-T-C

Position:

• chr4-157076225-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264428.9(GLRB):​c.-102T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 150,736 control chromosomes in the GnomAD database, including 14,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (14056 hom., cov: 32)
  • Exomes 𝑓: 0.36 (3 hom.)
• Consequence: GLRB ENST00000264428.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.764

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-157076225-T-C is Benign according to our data. Variant chr4-157076225-T-C is described in ClinVar as [Benign]. Clinvar id is 347911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRB	NM_000824.5	c.-102T>C		5_prime_UTR_variant	1/10	ENST00000264428.9	NP_000815.1
GLRB	NM_001166061.2	c.-102T>C		5_prime_UTR_variant	1/9		NP_001159533.1
GLRB	XM_047450075.1	c.-102T>C		5_prime_UTR_variant	1/9		XP_047306031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRB	ENST00000264428.9	c.-102T>C		5_prime_UTR_variant	1/10	1	NM_000824.5	ENSP00000264428	P1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59128 AN: 150576 Hom.: 14013 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.376

GnomAD4 exome AF: 0.360 AC: 18 AN: 50 Hom.: 3 Cov.: 0 AF XY: 0.357 AC XY: 15 AN XY: 42

Gnomad4 NFE exome AF: 0.360

GnomAD4 genome AF: 0.393 AC: 59222 AN: 150686 Hom.: 14056 Cov.: 32 AF XY: 0.388 AC XY: 28563 AN XY: 73616

Gnomad4 AFR AF: 0.671

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.440

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.374

Alfa AF: 0.328 Hom.: 1271

Bravo AF: 0.409

Asia WGS AF: 0.419 AC: 1422 AN: 3404

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs3822160; hg19: chr4-157997377;