rs373895476

Variant names:

• chr4-157170596-GAAC-G
• rs373895476
• NM_000824.5:c.1368_1370delCAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.75
• Publications: 2 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, Labcorp Genetics (formerly Invitae), G2P
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	NM_000824.5	MANE Select	c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	NP_000815.1	P48167-1
	GLRB	NM_001166060.2		c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	NP_001159532.1	P48167-1
	GLRB	NM_001440545.1		c.1074_1076delCAA	p.Asn358del	disruptive_inframe_deletion	Exon 11 of 11	NP_001427474.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRB	ENST00000264428.9	TSL:1 MANE Select	c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000264428.4	P48167-1
	GLRB	ENST00000509282.1	TSL:1	c.1368_1370delCAA	p.Asn456del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000427186.1	P48167-1
	GLRB	ENST00000960009.1		c.1434_1436delCAA	p.Asn478del	disruptive_inframe_deletion	Exon 11 of 11	ENSP00000630068.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152036 Hom.: 0 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74388

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

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000306

EpiCase AF: 0.000655

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperekplexia (1)
-	1	-	Hyperekplexia 2 (1)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

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