4-47320173-T-C

Position:

• chr4-47320173-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000812.4(GABRB1):​c.508T>C​(p.Leu170Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.986 in 1,607,758 control chromosomes in the GnomAD database, including 781,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71759 hom., cov: 31)
  • Exomes 𝑓: 0.99 (709777 hom.)
• Consequence: GABRB1 NM_000812.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.23

Genes affected

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) 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 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-47320173-T-C is Benign according to our data. Variant chr4-47320173-T-C is described in ClinVar as [Benign]. Clinvar id is 1642812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRB1	NM_000812.4	c.508T>C	p.Leu170Leu	synonymous_variant	5/9	ENST00000295454.8	NP_000803.2
GABRB1	XM_024453976.2	c.409T>C	p.Leu137Leu	synonymous_variant	5/9		XP_024309744.1
GABRB1	XM_024453977.2	c.409T>C	p.Leu137Leu	synonymous_variant	6/10		XP_024309745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB1	ENST00000295454.8	c.508T>C	p.Leu170Leu	synonymous_variant	5/9	1	NM_000812.4	ENSP00000295454.3
GABRB1	ENST00000510909.1	n.*176T>C		non_coding_transcript_exon_variant	4/5	4		ENSP00000426766.1
GABRB1	ENST00000510909.1	n.*176T>C		3_prime_UTR_variant	4/5	4		ENSP00000426766.1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147638 AN: 152190 Hom.: 71710 Cov.: 31

Gnomad AFR AF: 0.919

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.976

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.996

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.989

Gnomad OTH AF: 0.976

GnomAD3 exomes AF: 0.986 AC: 247796 AN: 251420 Hom.: 122160 AF XY: 0.987 AC XY: 134069 AN XY: 135878

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.988

Gnomad ASJ exome AF: 0.976

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.996

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.988

Gnomad OTH exome AF: 0.985

GnomAD4 exome AF: 0.987 AC: 1437241 AN: 1455450 Hom.: 709777 Cov.: 35 AF XY: 0.988 AC XY: 715692 AN XY: 724532

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.988

Gnomad4 ASJ exome AF: 0.977

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.996

Gnomad4 FIN exome AF: 0.998

Gnomad4 NFE exome AF: 0.989

Gnomad4 OTH exome AF: 0.982

GnomAD4 genome AF: 0.970 AC: 147744 AN: 152308 Hom.: 71759 Cov.: 31 AF XY: 0.971 AC XY: 72303 AN XY: 74460

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.985

Gnomad4 ASJ AF: 0.976

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.996

Gnomad4 FIN AF: 0.998

Gnomad4 NFE AF: 0.989

Gnomad4 OTH AF: 0.976

Alfa AF: 0.979 Hom.: 31795

Bravo AF: 0.966

Asia WGS AF: 0.994 AC: 3456 AN: 3478

EpiCase AF: 0.987

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs4482737; hg19: chr4-47322190;