Genetic Variant GLRA2:c.931-6_931-3dupTCTC (chrX-14690691-G-GTCTC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_StrongBP6BS2

The NM_002063.4(GLRA2):c.931-6_931-3dupTCTC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 924,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00040 ( 0 hom. 69 hem. )

Consequence

GLRA2
NM_002063.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.590

Variant links:

Genes affected

GLRA2 (HGNC:4327): (glycine receptor alpha 2) The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

GLRA2 links:

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11037528 fraction of the gene. Cryptic splice site detected, with MaxEntScore 14, offset of 0 (no position change), new splice context is: tctctctctctctctctcAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant X-14690691-G-GTCTC is Benign according to our data. Variant chrX-14690691-G-GTCTC is described in ClinVar as [Likely_benign]. Clinvar id is 3054739.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA2	NM_002063.4 link	c.931-6_931-3dupTCTC		splice_acceptor_variant, intron_variant	Intron 7 of 8	ENST00000218075.9	NP_002054.1	P23416-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA2	ENST00000218075.9 link	c.931-6_931-3dupTCTC		splice_acceptor_variant, intron_variant	Intron 7 of 8	1	NM_002063.4	ENSP00000218075.4		P23416-1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

109130

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

31858

show subpopulations

Gnomad AFR

AF:

0.0000671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000668

Gnomad OTH

AF:

0.000691

GnomAD3 exomes

AF:

0.000314

AC:

AN:

124260

Hom.:

AF XY:

0.000257

AC XY:

AN XY:

38956

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000640

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000402

AC:

328

AN:

815601

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

AN XY:

237923

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000652

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000505

Gnomad4 OTH exome

AF:

0.000568

GnomAD4 genome

AF:

0.000348

AC:

AN:

109173

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

31911

show subpopulations

Gnomad4 AFR

AF:

0.0000669

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000668

Gnomad4 OTH

AF:

0.000682

Bravo

AF:

0.000264

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GLRA2-related disorder

Benign:1

May 26, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over