5-161895648-T-C

Variant names:

• chr5-161895648-T-C
• rs78782356
• NM_001127644.2:c.857-18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127644.2(GABRA1):​c.857-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 1,595,954 control chromosomes in the GnomAD database, including 3,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (351 hom., cov: 31)
  • Exomes 𝑓: 0.064 (3136 hom.)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.28
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-161895648-T-C is Benign according to our data. Variant chr5-161895648-T-C is described in ClinVar as Benign. ClinVar VariationId is 256816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	NM_001127644.2	MANE Select	c.857-18T>C		intron	N/A	NP_001121116.1	P14867
	GABRA1	NM_000806.5		c.857-18T>C		intron	N/A	NP_000797.2	A8K177
	GABRA1	NM_001127643.2		c.857-18T>C		intron	N/A	NP_001121115.1	P14867

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.857-18T>C		intron	N/A	ENSP00000377517.4	P14867
	GABRA1	ENST00000023897.10	TSL:1	c.857-18T>C		intron	N/A	ENSP00000023897.6	P14867
	GABRA1	ENST00000428797.7	TSL:1	c.857-18T>C		intron	N/A	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9438 AN: 149568 Hom.: 344 Cov.: 31

Gnomad AFR AF: 0.0519

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0824

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0858

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0733

GnomAD2 exomes AF: 0.0922 AC: 18562 AN: 201228 AF XY: 0.0936

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0948

Gnomad FIN exome AF: 0.0657

Gnomad NFE exome AF: 0.0806

Gnomad OTH exome AF: 0.0934

GnomAD4 exome AF: 0.0637 AC: 92186 AN: 1446288 Hom.: 3136 Cov.: 34 AF XY: 0.0651 AC XY: 46812 AN XY: 719592

African (AFR) AF: 0.0560 AC: 1855 AN: 33136

American (AMR) AF: 0.100 AC: 4409 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2856 AN: 25950

East Asian (EAS) AF: 0.104 AC: 4092 AN: 39440

South Asian (SAS) AF: 0.105 AC: 8927 AN: 85416

European-Finnish (FIN) AF: 0.0518 AC: 2732 AN: 52696

Middle Eastern (MID) AF: 0.131 AC: 751 AN: 5736

European-Non Finnish (NFE) AF: 0.0567 AC: 62401 AN: 1100080

Other (OTH) AF: 0.0696 AC: 4163 AN: 59838

GnomAD4 genome AF: 0.0632 AC: 9459 AN: 149666 Hom.: 351 Cov.: 31 AF XY: 0.0643 AC XY: 4705 AN XY: 73142

African (AFR) AF: 0.0519 AC: 2078 AN: 40014

American (AMR) AF: 0.0824 AC: 1246 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3460

East Asian (EAS) AF: 0.0860 AC: 441 AN: 5128

South Asian (SAS) AF: 0.118 AC: 565 AN: 4788

European-Finnish (FIN) AF: 0.0447 AC: 467 AN: 10440

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0599 AC: 4038 AN: 67428

Other (OTH) AF: 0.0788 AC: 164 AN: 2080

Alfa AF: 0.0533 Hom.: 130

Bravo AF: 0.0673

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.0
DANN	Benign	0.52
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs78782356; hg19: chr5-161322654; COSMIC: COSV50108650; COSMIC: COSV50108650;