4-157170596-GAAC-G

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

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
GLRBNM_000824.5 linkc.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 Appris UniProt
GLRBENST00000264428.9 linkc.1368_1370delCAA p.Asn456del disruptive_inframe_deletion Exon 10 of 10 1 NM_000824.5 ENSP00000264428.4 P48167-1
GLRBENST00000509282.1 linkc.1368_1370delCAA p.Asn456del disruptive_inframe_deletion Exon 10 of 10 1 ENSP00000427186.1 P48167-1
GLRBENST00000541722.5 linkc.*163_*165delCAA 3_prime_UTR_variant Exon 9 of 9 5 ENSP00000441873.1 P48167-2
GLRBENST00000512619.5 linkc.*122_*124delCAA 3_prime_UTR_variant Exon 3 of 3 3 ENSP00000425433.1 D6RD86

Frequencies

GnomAD3 genomes
AF:
0.000270
AC:
41
AN:
152036
Hom.:
0
Cov.:
32
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:
99
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.:
0
AF XY:
0.000403
AC XY:
293
AN XY:
726970
show subpopulations
African (AFR)
AF:
0.000149
AC:
5
AN:
33458
American (AMR)
AF:
0.000336
AC:
15
AN:
44656
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26116
East Asian (EAS)
AF:
0.000101
AC:
4
AN:
39682
South Asian (SAS)
AF:
0.000104
AC:
9
AN:
86238
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000490
AC:
545
AN:
1111624
Other (OTH)
AF:
0.000248
AC:
15
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
30
60
89
119
149
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
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:
41
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74388
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41556
American (AMR)
AF:
0.0000655
AC:
1
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000574
AC:
39
AN:
67924
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
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

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

Other links and lift over

dbSNP: rs373895476; hg19: chr4-158091748; COSMIC: COSV100030166; API