rs368961588

Positions:

• chr1-2029976-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000378585.7(GABRD):​c.1060-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,612,156 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: GABRD ENST00000378585.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002511
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.96

Genes affected

GABRD (HGNC:4084): (gamma-aminobutyric acid type A receptor subunit delta) Gamma-aminobutyric acid (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. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015247136).
• BP6: Variant 1-2029976-C-T is Benign according to our data. Variant chr1-2029976-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460003.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5	c.1060-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000378585.7	NP_000806.2
GABRD	XM_011541194.4	c.1099-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011539496.1
GABRD	XM_017000936.2	c.1765-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016856425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7	c.1060-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000815.5	ENSP00000367848	P1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000448 AC: 111 AN: 247602 Hom.: 0 AF XY: 0.000520 AC XY: 70 AN XY: 134564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000589 AC: 860 AN: 1459782 Hom.: 2 Cov.: 32 AF XY: 0.000574 AC XY: 417 AN XY: 726120

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000666

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74514

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.000771

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000702 AC: 6

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000818

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -

Idiopathic generalized epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.35
DANN	Benign	0.55
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.015	T
MutationTaster	Benign	1.0	N
GERP RS		-6.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs368961588; hg19: chr1-1961415;