rs145400180

chr18-11752565-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001369387.1(GNAL):c.132C>T(p.Arg44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,610,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: GNAL NM_001369387.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.335

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 18-11752565-C-T is Benign according to our data. Variant chr18-11752565-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 526222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-11752565-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.335 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000184 (28/152244) while in subpopulation SAS AF= 0.000414 (2/4832). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAL	NM_001369387.1	c.132C>T	p.Arg44=	synonymous_variant	1/12	ENST00000423027.8
GNAL	NM_182978.4	c.377-288C>T		intron_variant		ENST00000334049.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAL	ENST00000423027.8	c.132C>T	p.Arg44=	synonymous_variant	1/12	1	NM_001369387.1	P1
GNAL	ENST00000535121.5	c.132C>T	p.Arg44=	synonymous_variant	2/13	1		P1
GNAL	ENST00000334049.11	c.377-288C>T		intron_variant		1	NM_182978.4
GNAL	ENST00000269162.9	c.132C>T	p.Arg44=	synonymous_variant	2/13	2		P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000303 AC: 74 AN: 244060 Hom.: 0 AF XY: 0.000362 AC XY: 48 AN XY: 132756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.000503

Gnomad EAS exome AF: 0.0000570

Gnomad SAS exome AF: 0.000993

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000355 AC: 518 AN: 1458096 Hom.: 0 Cov.: 31 AF XY: 0.000385 AC XY: 279 AN XY: 725410

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000730

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000780

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2022

- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	17
Dann	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs145400180; hg19: chr18-11752564;