dbSNP rs755545025: GLRA2:p.Asn198Lys (chrX-14607147-T-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4BP6_ModerateBS2

The NM_002063.4(GLRA2):c.594T>A(p.Asn198Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,185,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000039 ( 0 hom. 11 hem. )

Consequence

GLRA2
NM_002063.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.44

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

intellectual developmental disorder, X-linked, syndromic, Pilorge type
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

GLRA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.7002 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked, syndromic, Pilorge type.

BP4

Computational evidence support a benign effect (MetaRNN=0.40232465).

BP6

Variant X-14607147-T-A is Benign according to our data. Variant chrX-14607147-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3520641.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002063.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLRA2	NM_002063.4	MANE Select	c.594T>A	p.Asn198Lys	missense	Exon 6 of 9	NP_002054.1	P23416-1
GLRA2	NM_001118885.2		c.594T>A	p.Asn198Lys	missense	Exon 7 of 10	NP_001112357.1	P23416-1
GLRA2	NM_001118886.2		c.594T>A	p.Asn198Lys	missense	Exon 6 of 9	NP_001112358.1	P23416-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLRA2	ENST00000218075.9	TSL:1 MANE Select	c.594T>A	p.Asn198Lys	missense	Exon 6 of 9	ENSP00000218075.4	P23416-1
GLRA2	ENST00000355020.9	TSL:1	c.594T>A	p.Asn198Lys	missense	Exon 6 of 9	ENSP00000347123.4	P23416-2
GLRA2	ENST00000415367.2	TSL:3	n.845T>A		non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111827

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000337

AC:

AN:

177966

AF XY:

0.0000475

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000749

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1073567

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

341443

show subpopulations

African (AFR)

AF:

0.0000387

AC:

AN:

25837

American (AMR)

AF:

0.00

AC:

AN:

34735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19122

East Asian (EAS)

AF:

0.00

AC:

AN:

30062

South Asian (SAS)

AF:

0.00

AC:

AN:

52884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40489

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4063

European-Non Finnish (NFE)

AF:

0.0000499

AC:

AN:

821164

Other (OTH)

AF:

0.00

AC:

AN:

45211

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111827

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34035

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30779

American (AMR)

AF:

0.00

AC:

AN:

10480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6105

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53150

Other (OTH)

AF:

0.00

AC:

AN:

1499

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

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:

0.000142

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.80

PhyloP100

1.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.34

Sift

Benign

0.27

Sift4G

Benign

0.65

Polyphen

0.99

Vest4

0.77

MutPred

0.67

Gain of ubiquitination at N198 (P = 0.0258)

MVP

0.93

MPC

2.5

ClinPred

0.18

GERP RS

3.2

Varity_R

0.54

gMVP

0.91

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over