18-11855801-C-T

Variant names:

• chr18-11855801-C-T
• rs1249624
• NM_182978.4:c.723-6594C>T

Variant summary

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

The NM_182978.4(GNAL):​c.723-6594C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 151,876 control chromosomes in the GnomAD database, including 30,609 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 0.60 (30609 hom., cov: 32)
• Consequence: GNAL NM_182978.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 2 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

ENSG00000296678 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAL	NM_182978.4	c.723-6594C>T		intron_variant	Intron 5 of 11	ENST00000334049.11	NP_892023.1
GNAL	NM_001369387.1	c.492-6594C>T		intron_variant	Intron 5 of 11	ENST00000423027.8	NP_001356316.1
GNAL	NM_001142339.3	c.492-6594C>T		intron_variant	Intron 6 of 12		NP_001135811.1
GNAL	NM_001261443.2	c.492-6594C>T		intron_variant	Intron 6 of 12		NP_001248372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.723-6594C>T		intron_variant	Intron 5 of 11	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000423027.8	c.492-6594C>T		intron_variant	Intron 5 of 11	1	NM_001369387.1	ENSP00000408489.2

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90620 AN: 151758 Hom.: 30589 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.629

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

GnomAD4 genome AF: 0.597 AC: 90665 AN: 151876 Hom.: 30609 Cov.: 32 AF XY: 0.604 AC XY: 44826 AN XY: 74216

African (AFR) AF: 0.264 AC: 10910 AN: 41338

American (AMR) AF: 0.760 AC: 11590 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2218 AN: 3468

East Asian (EAS) AF: 0.559 AC: 2872 AN: 5140

South Asian (SAS) AF: 0.588 AC: 2834 AN: 4820

European-Finnish (FIN) AF: 0.869 AC: 9200 AN: 10584

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.720 AC: 48927 AN: 67958

Other (OTH) AF: 0.632 AC: 1332 AN: 2106

Alfa AF: 0.559 Hom.: 2009

Bravo AF: 0.575

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.21
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: rs1249624; hg19: chr18-11855800;