Genetic Variant NM_005458.8:c.*308A>C (chr9-98290276-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_005458.8(GABBR2):c.*308A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 94,938 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 1 hom., cov: 27)

Exomes 𝑓: 0.0035 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

GABBR2
NM_005458.8 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00

Publications

0 publications found

Variant links:

Genes affected

GABBR2 (HGNC:4507): (gamma-aminobutyric acid type B receptor subunit 2) The multi-pass membrane protein encoded by this gene belongs to the G-protein coupled receptor 3 family and GABA-B receptor subfamily. The GABA-B receptors inhibit neuronal activity through G protein-coupled second-messenger systems, which regulate the release of neurotransmitters, and the activity of ion channels and adenylyl cyclase. This receptor subunit forms an active heterodimeric complex with GABA-B receptor subunit 1, neither of which is effective on its own. Allelic variants of this gene have been associated with nicotine dependence.[provided by RefSeq, Jan 2010]

GABBR2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 59
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with poor language and loss of hand skills
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABBR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 9-98290276-T-G is Benign according to our data. Variant chr9-98290276-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1206699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005458.8. 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
	GABBR2	NM_005458.8	MANE Select	c.*308A>C		3_prime_UTR	Exon 19 of 19	NP_005449.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.*308A>C	3_prime_UTR	Exon 19 of 19	ENSP00000259455.2	O75899
GABBR2	ENST00000931526.1		c.*308A>C	3_prime_UTR	Exon 18 of 18	ENSP00000601585.1
GABBR2	ENST00000947376.1		c.*308A>C	downstream_gene	N/A	ENSP00000617435.1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

489

AN:

94920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00156

Gnomad AMR

AF:

0.00192

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00521

Gnomad SAS

AF:

0.00335

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.0168

Gnomad NFE

AF:

0.00433

Gnomad OTH

AF:

0.00570

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00350

AC:

AN:

14286

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

AN XY:

7448

show subpopulations

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

African (AFR)

AF:

0.00128

AC:

AN:

784

American (AMR)

AF:

0.00483

AC:

AN:

414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

694

East Asian (EAS)

AF:

0.00293

AC:

AN:

1364

South Asian (SAS)

AF:

0.00

AC:

AN:

132

European-Finnish (FIN)

AF:

0.0192

AC:

AN:

992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00248

AC:

AN:

8868

Other (OTH)

AF:

0.00210

AC:

AN:

954

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000134204), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.376

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00514

AC:

488

AN:

94938

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

220

AN XY:

46332

show subpopulations

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

African (AFR)

AF:

0.0103

AC:

201

AN:

19456

American (AMR)

AF:

0.00201

AC:

AN:

10422

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

2770

East Asian (EAS)

AF:

0.00523

AC:

AN:

3444

South Asian (SAS)

AF:

0.00306

AC:

AN:

3270

European-Finnish (FIN)

AF:

0.00293

AC:

AN:

6474

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00434

AC:

203

AN:

46826

Other (OTH)

AF:

0.00567

AC:

AN:

1412

⚠️ 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: 0.390

Heterozygous variant carriers

101

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.2

(source)

DANN

Benign

0.73

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

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

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