5-151886488-T-C

Variant names:

• chr5-151886488-T-C
• rs1549622
• NM_000171.4:c.252+233A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000171.4(GLRA1):​c.252+233A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,212 control chromosomes in the GnomAD database, including 3,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3343 hom., cov: 33)
• Consequence: GLRA1 NM_000171.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0550
• Publications: 3 publications found

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-151886488-T-C is Benign according to our data. Variant chr5-151886488-T-C is described in ClinVar as Benign. ClinVar VariationId is 1182659.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.252+233A>G		intron_variant	Intron 3 of 8	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.252+233A>G		intron_variant	Intron 3 of 8		NP_001139512.1
GLRA1	NM_001292000.2	c.3+233A>G		intron_variant	Intron 2 of 7		NP_001278929.1
GLRA1	XM_047417105.1	c.300+233A>G		intron_variant	Intron 3 of 8		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.252+233A>G		intron_variant	Intron 3 of 8	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.252+233A>G		intron_variant	Intron 3 of 8	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*10+233A>G		intron_variant	Intron 2 of 7	1		ENSP00000430595.1
GLRA1	ENST00000471351.2	n.535+233A>G		intron_variant	Intron 3 of 7	1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28581 AN: 152094 Hom.: 3343 Cov.: 33

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.188 AC: 28575 AN: 152212 Hom.: 3343 Cov.: 33 AF XY: 0.194 AC XY: 14415 AN XY: 74414

African (AFR) AF: 0.0507 AC: 2106 AN: 41556

American (AMR) AF: 0.205 AC: 3129 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 626 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1677 AN: 5174

South Asian (SAS) AF: 0.313 AC: 1509 AN: 4822

European-Finnish (FIN) AF: 0.304 AC: 3214 AN: 10570

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15725 AN: 68006

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.205 Hom.: 1955

Bravo AF: 0.173

Asia WGS AF: 0.305 AC: 1059 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 30, 2018

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	-0.91
CADD	Benign	1.0
DANN	Benign	0.42
PhyloP100		-0.055
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: rs1549622; hg19: chr5-151266049; COSMIC: COSV51013989;