Genetic Variant NM_014211.3:c.216C>G (chr5-170794274-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014211.3(GABRP):c.216C>G(p.Ile72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,459,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

GABRP
NM_014211.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0320

Variant links:

Genes affected

GABRP (HGNC:4089): (gamma-aminobutyric acid type A receptor subunit pi) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. The subunit encoded by this gene is expressed in several non-neuronal tissues including the uterus and ovaries. This subunit can assemble with known GABA A receptor subunits, and the presence of this subunit alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

GABRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRP	NM_014211.3 link	c.216C>G	p.Ile72Met	missense_variant	Exon 4 of 10	ENST00000265294.9	NP_055026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9 link	c.216C>G	p.Ile72Met	missense_variant	Exon 4 of 10	1	NM_014211.3	ENSP00000265294.4		O00591

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251112

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135714

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:

0.000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1459908

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726398

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.216C>G (p.I72M) alteration is located in exon 4 (coding exon 3) of the GABRP gene. This alteration results from a C to G substitution at nucleotide position 216, causing the isoleucine (I) at amino acid position 72 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;.;T;T;.;.

Eigen

Benign

0.059

Eigen_PC

Benign

-0.0089

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.69

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.024

MutationAssessor

Benign

1.9

.;.;.;L;L;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.6

D;N;D;N;N;N;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.013

D;D;D;D;D;D;T

Sift4G

Benign

0.063

T;D;T;D;D;T;T

Polyphen

1.0

.;.;.;D;D;D;.

Vest4

0.83, 0.82, 0.84, 0.83

MutPred

0.73

Gain of catalytic residue at I72 (P = 0.0119);Gain of catalytic residue at I72 (P = 0.0119);Gain of catalytic residue at I72 (P = 0.0119);Gain of catalytic residue at I72 (P = 0.0119);Gain of catalytic residue at I72 (P = 0.0119);Gain of catalytic residue at I72 (P = 0.0119);Gain of catalytic residue at I72 (P = 0.0119);

MVP

0.81

MPC

0.57

ClinPred

0.56

GERP RS

0.54

Varity_R

0.29

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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