chr18-11774501-A-G

Variant names:

• chr18-11774501-A-G
• rs2161961
• NM_182978.4:c.624+20556A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182978.4(GNAL):​c.624+20556A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 152,116 control chromosomes in the GnomAD database, including 8,959 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 0.31 (8959 hom., cov: 33)
• Consequence: GNAL NM_182978.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.261
• Publications: 3 publications found

Genes affected

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GNAL Gene-Disease associations (from GenCC):

• dystonia 25

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000286812 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4	c.624+20556A>G		intron_variant	Intron 4 of 11	ENST00000334049.11	NP_892023.1
GNAL	NM_001369387.1	c.393+20556A>G		intron_variant	Intron 4 of 11	ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.624+20556A>G		intron_variant	Intron 4 of 11	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000423027.8	c.393+20556A>G		intron_variant	Intron 4 of 11	1	NM_001369387.1	ENSP00000408489.2

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47147 AN: 151998 Hom.: 8942 Cov.: 33

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.294

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.310 AC: 47203 AN: 152116 Hom.: 8959 Cov.: 33 AF XY: 0.308 AC XY: 22886 AN XY: 74352

African (AFR) AF: 0.537 AC: 22300 AN: 41494

American (AMR) AF: 0.190 AC: 2904 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3468

East Asian (EAS) AF: 0.322 AC: 1662 AN: 5158

South Asian (SAS) AF: 0.289 AC: 1390 AN: 4812

European-Finnish (FIN) AF: 0.165 AC: 1744 AN: 10590

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15307 AN: 67994

Other (OTH) AF: 0.292 AC: 617 AN: 2114

Alfa AF: 0.257 Hom.: 894

Bravo AF: 0.322

Asia WGS AF: 0.268 AC: 931 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.88
DANN	Benign	0.49
PhyloP100		-0.26
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: rs2161961; hg19: chr18-11774500;