5-161293870-G-A

Variant names:

• chr5-161293870-G-A
• rs34906738
• NM_001371727.1:c.*211C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001371727.1(GABRB2):​c.*211C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 545,512 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (47 hom., cov: 32)
  • Exomes 𝑓: 0.028 (197 hom.)
• Consequence: GABRB2 NM_001371727.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.430
• Publications: 3 publications found

Genes affected

GABRB2 (HGNC:4082): (gamma-aminobutyric acid type A receptor subunit beta2) 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 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion. [provided by RefSeq, Jul 2008]

GABRB2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 92

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P
• undetermined early-onset epileptic encephalopathy

  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=-0.65).
• BP6: Variant 5-161293870-G-A is Benign according to our data. Variant chr5-161293870-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1217644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0222 (3373/152242) while in subpopulation NFE AF = 0.0357 (2425/68002). AF 95% confidence interval is 0.0345. There are 47 homozygotes in GnomAd4. There are 1557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3373 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB2	NM_001371727.1	c.*211C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000393959.6	NP_001358656.1
GABRB2	NM_021911.3	c.*211C>T		3_prime_UTR_variant	Exon 11 of 11		NP_068711.1
GABRB2	NM_000813.3	c.*211C>T		3_prime_UTR_variant	Exon 10 of 10		NP_000804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB2	ENST00000393959.6	c.*211C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_001371727.1	ENSP00000377531.1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3373 AN: 152124 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0272

GnomAD4 exome AF: 0.0280 AC: 10996 AN: 393270 Hom.: 197 Cov.: 3 AF XY: 0.0275 AC XY: 5633 AN XY: 204642

African (AFR) AF: 0.00706 AC: 82 AN: 11608

American (AMR) AF: 0.0186 AC: 291 AN: 15656

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 212 AN: 12550

East Asian (EAS) AF: 0.00 AC: 0 AN: 28432

South Asian (SAS) AF: 0.00988 AC: 342 AN: 34622

European-Finnish (FIN) AF: 0.0223 AC: 604 AN: 27056

Middle Eastern (MID) AF: 0.0244 AC: 43 AN: 1764

European-Non Finnish (NFE) AF: 0.0367 AC: 8733 AN: 238244

Other (OTH) AF: 0.0295 AC: 689 AN: 23338

GnomAD4 genome AF: 0.0222 AC: 3373 AN: 152242 Hom.: 47 Cov.: 32 AF XY: 0.0209 AC XY: 1557 AN XY: 74438

African (AFR) AF: 0.00647 AC: 269 AN: 41564

American (AMR) AF: 0.0198 AC: 303 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4826

European-Finnish (FIN) AF: 0.0202 AC: 214 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0357 AC: 2425 AN: 68002

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0206 Hom.: 13

Bravo AF: 0.0217

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Likely 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	-0.65
CADD	Benign	4.2
DANN	Benign	0.56
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

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: rs34906738; hg19: chr5-160720877;