chr18-11689626-G-T

Variant names:

• chr18-11689626-G-T
• rs956895925
• NM_182978.4:c.63G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_182978.4(GNAL):​c.63G>T​(p.Ala21Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAL NM_182978.4 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.595
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=0.595 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182978.4. 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
	GNAL	NM_182978.4	MANE Select	c.63G>T	p.Ala21Ala	synonymous	Exon 1 of 12	NP_892023.1	P38405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.63G>T	p.Ala21Ala	synonymous	Exon 1 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000585590.1	TSL:2	n.-64G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1208612 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 589464

African (AFR) AF: 0.00 AC: 0 AN: 23574

American (AMR) AF: 0.00 AC: 0 AN: 10394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16472

East Asian (EAS) AF: 0.00 AC: 0 AN: 27044

South Asian (SAS) AF: 0.00 AC: 0 AN: 49978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 999324

Other (OTH) AF: 0.00 AC: 0 AN: 49514

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.3
DANN	Benign	0.94
PhyloP100		0.59
PromoterAI		-0.068	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs956895925; hg19: chr18-11689625;