rs6290

Variant names:

• chr4-47406821-C-T
• rs6290
• NM_000812.4:c.975C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000812.4(GABRB1):​c.975C>T​(p.Ala325Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0832 in 1,613,950 control chromosomes in the GnomAD database, including 6,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (999 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5518 hom.)
• Consequence: GABRB1 NM_000812.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.472
• Publications: 19 publications found

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]

GABRB1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 45

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 4-47406821-C-T is Benign according to our data. Variant chr4-47406821-C-T is described in ClinVar as Benign. ClinVar VariationId is 1600634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB1	NM_000812.4	c.975C>T	p.Ala325Ala	synonymous_variant	Exon 8 of 9	ENST00000295454.8	NP_000803.2
GABRB1	XM_024453976.2	c.876C>T	p.Ala292Ala	synonymous_variant	Exon 8 of 9		XP_024309744.1
GABRB1	XM_024453977.2	c.876C>T	p.Ala292Ala	synonymous_variant	Exon 9 of 10		XP_024309745.1
GABRB1	XM_017007985.2	c.324C>T	p.Ala108Ala	synonymous_variant	Exon 4 of 5		XP_016863474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB1	ENST00000295454.8	c.975C>T	p.Ala325Ala	synonymous_variant	Exon 8 of 9	1	NM_000812.4	ENSP00000295454.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15875 AN: 152004 Hom.: 992 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0446

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0733

Gnomad OTH AF: 0.0903

GnomAD2 exomes AF: 0.0910 AC: 22873 AN: 251382 AF XY: 0.0934

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.0268

Gnomad ASJ exome AF: 0.0566

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0752

Gnomad OTH exome AF: 0.0771

GnomAD4 exome AF: 0.0809 AC: 118332 AN: 1461828 Hom.: 5518 Cov.: 34 AF XY: 0.0826 AC XY: 60056 AN XY: 727216

African (AFR) AF: 0.171 AC: 5738 AN: 33480

American (AMR) AF: 0.0286 AC: 1277 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0546 AC: 1428 AN: 26134

East Asian (EAS) AF: 0.124 AC: 4906 AN: 39698

South Asian (SAS) AF: 0.146 AC: 12635 AN: 86258

European-Finnish (FIN) AF: 0.108 AC: 5744 AN: 53418

Middle Eastern (MID) AF: 0.0695 AC: 401 AN: 5768

European-Non Finnish (NFE) AF: 0.0728 AC: 80920 AN: 1111954

Other (OTH) AF: 0.0875 AC: 5283 AN: 60396

GnomAD4 genome AF: 0.105 AC: 15904 AN: 152122 Hom.: 999 Cov.: 32 AF XY: 0.107 AC XY: 7933 AN XY: 74380

African (AFR) AF: 0.170 AC: 7034 AN: 41478

American (AMR) AF: 0.0445 AC: 680 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3468

East Asian (EAS) AF: 0.143 AC: 742 AN: 5174

South Asian (SAS) AF: 0.144 AC: 693 AN: 4814

European-Finnish (FIN) AF: 0.115 AC: 1218 AN: 10572

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0733 AC: 4986 AN: 68008

Other (OTH) AF: 0.0898 AC: 190 AN: 2116

Alfa AF: 0.0799 Hom.: 1188

Bravo AF: 0.100

Asia WGS AF: 0.135 AC: 470 AN: 3478

EpiCase AF: 0.0696

EpiControl AF: 0.0721

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.4
DANN	Benign	0.67
PhyloP100		0.47
Mutation Taster		=99/1	polymorphism (auto)

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: rs6290; hg19: chr4-47408838; COSMIC: COSV54981930; COSMIC: COSV54981930;