4-47320173-T-C

Variant names:

• chr4-47320173-T-C
• rs4482737
• NM_000812.4:c.508T>C

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. L170L) has been classified as Likely 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
• Publications: 16 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)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000812.4. 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
	GABRB1	NM_000812.4	MANE Select	c.508T>C	p.Leu170Leu	synonymous	Exon 5 of 9	NP_000803.2	X5DNL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB1	ENST00000295454.8	TSL:1 MANE Select	c.508T>C	p.Leu170Leu	synonymous	Exon 5 of 9	ENSP00000295454.3	P18505-1
	GABRB1	ENST00000510909.1	TSL:4	n.*176T>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000426766.1	P18505-2
	GABRB1	ENST00000510909.1	TSL:4	n.*176T>C		3_prime_UTR	Exon 4 of 5	ENSP00000426766.1	P18505-2

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

GnomAD2 exomes AF: 0.986 AC: 247796 AN: 251420 AF XY: 0.987

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 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

African (AFR) AF: 0.916 AC: 30531 AN: 33328

American (AMR) AF: 0.988 AC: 44169 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.977 AC: 25487 AN: 26100

East Asian (EAS) AF: 1.00 AC: 39662 AN: 39664

South Asian (SAS) AF: 0.996 AC: 85838 AN: 86170

European-Finnish (FIN) AF: 0.998 AC: 53311 AN: 53416

Middle Eastern (MID) AF: 0.952 AC: 5486 AN: 5764

European-Non Finnish (NFE) AF: 0.989 AC: 1093593 AN: 1106044

Other (OTH) AF: 0.982 AC: 59164 AN: 60242

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

African (AFR) AF: 0.919 AC: 38192 AN: 41552

American (AMR) AF: 0.985 AC: 15062 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 3388 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5177 AN: 5180

South Asian (SAS) AF: 0.996 AC: 4810 AN: 4828

European-Finnish (FIN) AF: 0.998 AC: 10599 AN: 10622

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.989 AC: 67259 AN: 68040

Other (OTH) AF: 0.976 AC: 2063 AN: 2114

Alfa AF: 0.978 Hom.: 32115

Bravo AF: 0.966

Asia WGS AF: 0.994 AC: 3456 AN: 3478

EpiCase AF: 0.987

EpiControl AF: 0.986

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		2.2
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4482737; hg19: chr4-47322190; COSMIC: COSV108119701;