chr5-161898928-A-C

Variant names:

• chr5-161898928-A-C
• rs998754
• NM_001127644.2:c.*1506A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001127644.2(GABRA1):​c.*1506A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 152,354 control chromosomes in the GnomAD database, including 27,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.60 (27596 hom., cov: 32)
  • Exomes 𝑓: 0.50 (52 hom.)
• Consequence: GABRA1 NM_001127644.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51
• Publications: 16 publications found

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRA1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 19

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 13

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-161898928-A-C is Benign according to our data. Variant chr5-161898928-A-C is described in ClinVar as Benign. ClinVar VariationId is 352614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127644.2. 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
	GABRA1	NM_001127644.2	MANE Select	c.*1506A>C		3_prime_UTR	Exon 10 of 10	NP_001121116.1
	GABRA1	NM_000806.5		c.*1506A>C		3_prime_UTR	Exon 11 of 11	NP_000797.2
	GABRA1	NM_001127643.2		c.*1506A>C		3_prime_UTR	Exon 11 of 11	NP_001121115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.*1506A>C		3_prime_UTR	Exon 10 of 10	ENSP00000377517.4
	GABRA1	ENST00000428797.7	TSL:1	c.*1506A>C		3_prime_UTR	Exon 11 of 11	ENSP00000393097.2
	GABRA1	ENST00000437025.6	TSL:1	c.*1506A>C		3_prime_UTR	Exon 10 of 10	ENSP00000415441.2

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90860 AN: 151804 Hom.: 27561 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.505 AC: 218 AN: 432 Hom.: 52 Cov.: 0 AF XY: 0.496 AC XY: 129 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.505 AC: 215 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.599 AC: 90949 AN: 151922 Hom.: 27596 Cov.: 32 AF XY: 0.596 AC XY: 44265 AN XY: 74246

African (AFR) AF: 0.563 AC: 23336 AN: 41442

American (AMR) AF: 0.684 AC: 10431 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2044 AN: 3468

East Asian (EAS) AF: 0.463 AC: 2390 AN: 5160

South Asian (SAS) AF: 0.553 AC: 2662 AN: 4812

European-Finnish (FIN) AF: 0.539 AC: 5697 AN: 10562

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42500 AN: 67908

Other (OTH) AF: 0.593 AC: 1249 AN: 2108

Alfa AF: 0.616 Hom.: 68578

Bravo AF: 0.605

Asia WGS AF: 0.524 AC: 1816 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, idiopathic generalized, susceptibility to, 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs998754; hg19: chr5-161325934; COSMIC: COSV50100437; COSMIC: COSV50100437;