Genetic Variant GLRB:c.122+230T>C (chr4-157078376-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.335

Publications

3 publications found

Variant links:

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

GLRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRB	NM_000824.5 link	c.122+230T>C		intron_variant	Intron 2 of 9	ENST00000264428.9	NP_000815.1	P48167-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRB	ENST00000264428.9 link	c.122+230T>C		intron_variant	Intron 2 of 9	1	NM_000824.5	ENSP00000264428.4		P48167-1

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

31989

AN:

151464

Hom.:

3525

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.221

AC:

304

AN:

1374

American (AMR)

AF:

0.136

AC:

AN:

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:

AN:

Middle Eastern (MID)

AF:

0.220

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.177

AC:

12943

AN:

73294

Other (OTH)

AF:

0.205

AC:

517

AN:

2518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

610

1221

1831

2442

3052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.211

AC:

32002

AN:

151576

Hom.:

3526

Cov.:

AF XY:

0.213

AC XY:

15790

AN XY:

74098

show subpopulations

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.181

AC:

12280

AN:

67852

Other (OTH)

AF:

0.204

AC:

428

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1247

2494

3740

4987

6234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.7

(source)

DANN

Benign

0.77

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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chr4-157078376-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over