chr5-170808696-T-C

Position:

• chr5-170808696-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014211.3(GABRP):​c.776T>C​(p.Leu259Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRP NM_014211.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRP	NM_014211.3	c.776T>C	p.Leu259Ser	missense_variant	8/10	ENST00000265294.9	NP_055026.1
GABRP	NM_001291985.2	c.776T>C	p.Leu259Ser	missense_variant	8/9		NP_001278914.1
GABRP	XM_024446012.2	c.776T>C	p.Leu259Ser	missense_variant	8/10		XP_024301780.1
GABRP	XM_005265872.2	c.539T>C	p.Leu180Ser	missense_variant	6/8		XP_005265929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRP	ENST00000265294.9	c.776T>C	p.Leu259Ser	missense_variant	8/10	1	NM_014211.3	ENSP00000265294	P1
GABRP	ENST00000518525.5	c.776T>C	p.Leu259Ser	missense_variant	9/11	5		ENSP00000430100	P1
GABRP	ENST00000519598.1	c.776T>C	p.Leu259Ser	missense_variant	8/10	5		ENSP00000430772
GABRP	ENST00000519385.5	c.776T>C	p.Leu259Ser	missense_variant	8/9	2		ENSP00000430727

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.776T>C (p.L259S) alteration is located in exon 8 (coding exon 7) of the GABRP gene. This alteration results from a T to C substitution at nucleotide position 776, causing the leucine (L) at amino acid position 259 to be replaced by a serine (S). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.94
MutPred		0.75		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.95
MPC		0.67
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.43
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-170235700;