rs869312861

Variant names:

• chr5-161334830-G-A
• rs869312861
• NM_001371727.1:c.754C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-161334830-G-A
• chr5-161334830-G-C
• chr5-161334830-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001371727.1(GABRB2):​c.754C>T​(p.Pro252Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P252L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB2 NM_001371727.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.87
• Publications: 1 publications found

Genes affected

GABRB2 (HGNC:4082): (gamma-aminobutyric acid type A receptor subunit beta2) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion. [provided by RefSeq, Jul 2008]

GABRB2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 92

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001371727.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-161334829-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1057864.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 5-161334830-G-A is Pathogenic according to our data. Variant chr5-161334830-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1338859.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371727.1. 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
	GABRB2	NM_001371727.1	MANE Select	c.754C>T	p.Pro252Ser	missense	Exon 7 of 10	NP_001358656.1	P47870-2
	GABRB2	NM_021911.3		c.754C>T	p.Pro252Ser	missense	Exon 8 of 11	NP_068711.1	P47870-2
	GABRB2	NM_000813.3		c.754C>T	p.Pro252Ser	missense	Exon 8 of 10	NP_000804.1	P47870-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB2	ENST00000393959.6	TSL:1 MANE Select	c.754C>T	p.Pro252Ser	missense	Exon 7 of 10	ENSP00000377531.1	P47870-2
	GABRB2	ENST00000353437.10	TSL:1	c.754C>T	p.Pro252Ser	missense	Exon 8 of 10	ENSP00000274546.6	P47870-1
	GABRB2	ENST00000520240.5	TSL:1	c.754C>T	p.Pro252Ser	missense	Exon 8 of 10	ENSP00000429320.1	P47870-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy 92 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.93		Gain of catalytic residue at P252 (P = 0.1295)
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.99
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs869312861; hg19: chr5-160761837;