Genetic Variant GABRD:p.Pro277Pro (chr1-2029250-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000815.5(GABRD):c.831C>T(p.Pro277Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,563,878 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 34)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

GABRD
NM_000815.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.33

Publications

1 publications found

Variant links:

Genes affected

GABRD (HGNC:4084): (gamma-aminobutyric acid type A receptor subunit delta) Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

GABRD Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
epilepsy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
epilepsy, idiopathic generalized, susceptibility to, 10
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GABRD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049646497).

BP6

Variant 1-2029250-C-T is Benign according to our data. Variant chr1-2029250-C-T is described in ClinVar as Benign. ClinVar VariationId is 460015.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.34 with no splicing effect.

BS2

High AC in GnomAd4 at 152 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GABRD	NM_000815.5 link	c.831C>T	p.Pro277Pro	synonymous_variant	Exon 7 of 9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2 link	c.1536C>T	p.Pro512Pro	synonymous_variant	Exon 6 of 8		XP_016856425.1
GABRD	XM_011541194.4 link	c.870C>T	p.Pro290Pro	synonymous_variant	Exon 7 of 9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 link	c.831C>T	p.Pro277Pro	synonymous_variant	Exon 7 of 9	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes

AF:

0.000998

AC:

152

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000230

AC:

AN:

173744

AF XY:

0.000205

show subpopulations

Gnomad AFR exome

AF:

0.00348

Gnomad AMR exome

AF:

0.0000764

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000792

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000138

Gnomad OTH exome

AF:

0.000206

GnomAD4 exome

AF:

0.0000772

AC:

109

AN:

1411496

Hom.:

Cov.:

AF XY:

0.0000774

AC XY:

AN XY:

697930

show subpopulations

African (AFR)

AF:

0.00265

AC:

AN:

32100

American (AMR)

AF:

0.000135

AC:

AN:

37172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.0000272

AC:

AN:

36780

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000735

AC:

AN:

1088242

Other (OTH)

AF:

0.000153

AC:

AN:

58756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000997

AC:

152

AN:

152382

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00361

AC:

150

AN:

41588

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000615

Hom.:

Bravo

AF:

0.00106

ESP6500AA

AF:

0.00344

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000274

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy

Benign:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_noAF

Benign

-0.46

CADD

Benign

2.0

(source)

DANN

Benign

0.78

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0050

PhyloP100

-2.3

GERP RS

-3.4

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over