NM_000824.5:c.1368_1370delCAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS1

The NM_000824.5(GLRB):c.1368_1370delCAA(p.Asn456del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000394 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

GLRB
NM_000824.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.75

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000824.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 4-157170596-GAAC-G is Benign according to our data. Variant chr4-157170596-GAAC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 347928.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000269 (41/152154) while in subpopulation NFE AF = 0.000574 (39/67924). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRB	NM_000824.5 link	c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	ENST00000264428.9	NP_000815.1	P48167-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLRB	ENST00000264428.9 link	c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	1	NM_000824.5	ENSP00000264428.4	P48167-1
GLRB	ENST00000509282.1 link	c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	1		ENSP00000427186.1	P48167-1
GLRB	ENST00000541722.5 link	c.163_165delCAA		3_prime_UTR_variant	Exon 9 of 9	5		ENSP00000441873.1	P48167-2
GLRB	ENST00000512619.5 link	c.122_124delCAA		3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000425433.1	D6RD86

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000574

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000394

AC:

AN:

251068

AF XY:

0.000391

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000661

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000406

AC:

594

AN:

1461330

Hom.:

AF XY:

0.000403

AC XY:

293

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33458

American (AMR)

AF:

0.000336

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.000101

AC:

AN:

39682

South Asian (SAS)

AF:

0.000104

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000490

AC:

545

AN:

1111624

Other (OTH)

AF:

0.000248

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000269

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000574

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000306

EpiCase

AF:

0.000655

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperekplexia 2

Uncertain:1

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1368_1370del, results in the deletion of 1 amino acid(s) of the GLRB protein (p.Asn456del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs373895476, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with GLRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 347928). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Hyperekplexia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Mutation Taster

=45/55

disease causing

(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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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