6-29608616-A-G

Variant names:

• chr6-29608616-A-G
• rs29230
• NM_001470.4:c.1977T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001470.4(GABBR1):​c.1977T>C​(p.Phe659Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,484 control chromosomes in the GnomAD database, including 27,023 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2425 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24598 hom.)
• Consequence: GABBR1 NM_001470.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 55 publications found

Genes affected

GABBR1 (HGNC:4070): (gamma-aminobutyric acid type B receptor subunit 1) This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

GABBR1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language delay and variable cognitive abnormalities

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.137).
• BP7: Synonymous conserved (PhyloP=2.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR1	NM_001470.4	MANE Select	c.1977T>C	p.Phe659Phe	synonymous	Exon 16 of 23	NP_001461.1
	GABBR1	NM_021904.4		c.1791T>C	p.Phe597Phe	synonymous	Exon 15 of 22	NP_068704.2
	GABBR1	NM_021903.3		c.1626T>C	p.Phe542Phe	synonymous	Exon 11 of 18	NP_068703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR1	ENST00000377034.9	TSL:1 MANE Select	c.1977T>C	p.Phe659Phe	synonymous	Exon 16 of 23	ENSP00000366233.4
	GABBR1	ENST00000377012.9	TSL:1	c.1626T>C	p.Phe542Phe	synonymous	Exon 11 of 18	ENSP00000366211.4
	GABBR1	ENST00000476670.3	TSL:4	c.1992T>C	p.Phe664Phe	synonymous	Exon 16 of 23	ENSP00000417332.2

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25555 AN: 152022 Hom.: 2424 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.182 AC: 44768 AN: 246210 AF XY: 0.190

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.244

Gnomad FIN exome AF: 0.0716

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.176 AC: 257453 AN: 1460344 Hom.: 24598 Cov.: 32 AF XY: 0.181 AC XY: 131750 AN XY: 726490

African (AFR) AF: 0.155 AC: 5199 AN: 33462

American (AMR) AF: 0.158 AC: 7071 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 5905 AN: 26122

East Asian (EAS) AF: 0.225 AC: 8923 AN: 39696

South Asian (SAS) AF: 0.307 AC: 26481 AN: 86190

European-Finnish (FIN) AF: 0.0768 AC: 4019 AN: 52318

Middle Eastern (MID) AF: 0.340 AC: 1960 AN: 5768

European-Non Finnish (NFE) AF: 0.167 AC: 186021 AN: 1111734

Other (OTH) AF: 0.197 AC: 11874 AN: 60368

GnomAD4 genome AF: 0.168 AC: 25565 AN: 152140 Hom.: 2425 Cov.: 32 AF XY: 0.170 AC XY: 12615 AN XY: 74394

African (AFR) AF: 0.154 AC: 6396 AN: 41486

American (AMR) AF: 0.169 AC: 2582 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3466

East Asian (EAS) AF: 0.256 AC: 1326 AN: 5176

South Asian (SAS) AF: 0.317 AC: 1525 AN: 4816

European-Finnish (FIN) AF: 0.0724 AC: 768 AN: 10610

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.170 AC: 11537 AN: 67976

Other (OTH) AF: 0.208 AC: 441 AN: 2116

Alfa AF: 0.175 Hom.: 8101

Bravo AF: 0.175

Asia WGS AF: 0.232 AC: 807 AN: 3478

EpiCase AF: 0.191

EpiControl AF: 0.187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.9
DANN	Benign	0.68
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs29230; hg19: chr6-29576393; COSMIC: COSV63542238; COSMIC: COSV63542238;