rs10857299

Variant names:

• chr4-157078376-T-C
• rs10857299
• NM_000824.5:c.122+230T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000824.5(GLRB):​c.122+230T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 231,340 control chromosomes in the GnomAD database, including 4,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3526 hom., cov: 31)
  • Exomes 𝑓: 0.18 (1466 hom.)
• Consequence: GLRB NM_000824.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.335
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-157078376-T-C is Benign according to our data. Variant chr4-157078376-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242317.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 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.122+230T>C		intron	N/A	NP_000815.1
	GLRB	NM_001166060.2		c.122+230T>C		intron	N/A	NP_001159532.1
	GLRB	NM_001440545.1		c.-234+230T>C		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.122+230T>C		intron	N/A	ENSP00000264428.4
	GLRB	ENST00000509282.1	TSL:1	c.122+230T>C		intron	N/A	ENSP00000427186.1
	GLRB	ENST00000541722.5	TSL:5	c.122+230T>C		intron	N/A	ENSP00000441873.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31989 AN: 151464 Hom.: 3525 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.203

GnomAD4 exome AF: 0.183 AC: 14587 AN: 79764 Hom.: 1466 AF XY: 0.182 AC XY: 7023 AN XY: 38626

African (AFR) AF: 0.221 AC: 304 AN: 1374

American (AMR) AF: 0.136 AC: 12 AN: 88

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 112 AN: 506

East Asian (EAS) AF: 0.346 AC: 110 AN: 318

South Asian (SAS) AF: 0.367 AC: 559 AN: 1524

European-Finnish (FIN) AF: 0.100 AC: 1 AN: 10

Middle Eastern (MID) AF: 0.220 AC: 29 AN: 132

European-Non Finnish (NFE) AF: 0.177 AC: 12943 AN: 73294

Other (OTH) AF: 0.205 AC: 517 AN: 2518

GnomAD4 genome AF: 0.211 AC: 32002 AN: 151576 Hom.: 3526 Cov.: 31 AF XY: 0.213 AC XY: 15790 AN XY: 74098

African (AFR) AF: 0.248 AC: 10228 AN: 41248

American (AMR) AF: 0.182 AC: 2770 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3470

East Asian (EAS) AF: 0.318 AC: 1638 AN: 5156

South Asian (SAS) AF: 0.390 AC: 1868 AN: 4788

European-Finnish (FIN) AF: 0.174 AC: 1827 AN: 10512

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.181 AC: 12280 AN: 67852

Other (OTH) AF: 0.204 AC: 428 AN: 2098

Alfa AF: 0.192 Hom.: 930

Bravo AF: 0.210

Asia WGS AF: 0.324 AC: 1121 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.77
PhyloP100		-0.34
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: rs10857299; hg19: chr4-157999528;