NM_000824.5:c.*1181C>T

Variant names:

• chr4-157171909-C-T
• rs10517662
• NM_000824.5:c.*1181C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000824.5(GLRB):​c.*1181C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 151,778 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (590 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GLRB NM_000824.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.770
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 4-157171909-C-T is Benign according to our data. Variant chr4-157171909-C-T is described in ClinVar as Benign. ClinVar VariationId is 347948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 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.*1181C>T		3_prime_UTR	Exon 10 of 10	NP_000815.1
	GLRB	NM_001166060.2		c.*1181C>T		3_prime_UTR	Exon 10 of 10	NP_001159532.1
	GLRB	NM_001440545.1		c.*1181C>T		3_prime_UTR	Exon 11 of 11	NP_001427474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	ENST00000264428.9	TSL:1 MANE Select	c.*1181C>T		3_prime_UTR	Exon 10 of 10	ENSP00000264428.4
	GLRB	ENST00000960007.1		c.*1181C>T		3_prime_UTR	Exon 10 of 10	ENSP00000630066.1
	GLRB	ENST00000960008.1		c.*1181C>T		3_prime_UTR	Exon 11 of 11	ENSP00000630067.1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11562 AN: 151660 Hom.: 592 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0402

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0812

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0763 AC: 11575 AN: 151778 Hom.: 590 Cov.: 32 AF XY: 0.0769 AC XY: 5700 AN XY: 74164

African (AFR) AF: 0.140 AC: 5815 AN: 41498

American (AMR) AF: 0.0402 AC: 612 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3464

East Asian (EAS) AF: 0.0358 AC: 185 AN: 5166

South Asian (SAS) AF: 0.103 AC: 497 AN: 4822

European-Finnish (FIN) AF: 0.0517 AC: 546 AN: 10558

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0463 AC: 3136 AN: 67730

Other (OTH) AF: 0.0803 AC: 169 AN: 2104

Alfa AF: 0.0564 Hom.: 409

Bravo AF: 0.0778

Asia WGS AF: 0.0730 AC: 254 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperekplexia 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.6
DANN	Benign	0.76
PhyloP100		-0.77
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: rs10517662; hg19: chr4-158093061;