dbSNP rs769857211: GABRD:p.Ile28Met (chr1-2024957-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000815.5(GABRD):c.84C>G(p.Ile28Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I28I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.470

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23216441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GABRD	NM_000815.5 link	c.84C>G	p.Ile28Met	missense_variant	Exon 2 of 9	ENST00000378585.7	NP_000806.2
GABRD	XM_017000936.2 link	c.789C>G	p.Ile263Met	missense_variant	Exon 1 of 8		XP_016856425.1
GABRD	XM_011541194.4 link	c.123C>G	p.Ile41Met	missense_variant	Exon 2 of 9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 link	c.84C>G	p.Ile28Met	missense_variant	Exon 2 of 9	1	NM_000815.5	ENSP00000367848.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459906

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726320

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111226

Other (OTH)

AF:

0.00

AC:

AN:

60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;.;.;.;.;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.071

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.81

L;.;.;.;.;.

PhyloP100

-0.47

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.54

N;.;.;.;.;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.013

D;.;.;.;.;.

Sift4G

Benign

0.11

T;.;.;.;.;.

Polyphen

0.99

D;.;.;.;.;.

Vest4

0.49

MutPred

0.45

Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);.;

MVP

0.54

MPC

1.6

ClinPred

0.97

GERP RS

-4.2

PromoterAI

-0.0092

Neutral

(source)

Varity_R

0.089

gMVP

0.66

Mutation Taster

=78/22

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over