rs145400180

Variant names:

• chr18-11752565-C-T
• rs145400180
• NM_001369387.1:c.132C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001369387.1(GNAL):​c.132C>T​(p.Arg44Arg) 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:3
• Conservation: PhyloP100: -0.335
• Publications: 0 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 526222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369387.1. 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_001369387.1	MANE Plus Clinical	c.132C>T	p.Arg44Arg	synonymous	Exon 1 of 12	NP_001356316.1	A8K1Y9
	GNAL	NM_182978.4	MANE Select	c.377-288C>T		intron	N/A	NP_892023.1	P38405-2
	GNAL	NM_001142339.3		c.132C>T	p.Arg44Arg	synonymous	Exon 2 of 13	NP_001135811.1	A8K1Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.132C>T	p.Arg44Arg	synonymous	Exon 1 of 12	ENSP00000408489.2	P38405-1
	GNAL	ENST00000535121.5	TSL:1	c.132C>T	p.Arg44Arg	synonymous	Exon 2 of 13	ENSP00000439023.1	P38405-1
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.377-288C>T		intron	N/A	ENSP00000334051.5	P38405-2

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

GnomAD2 exomes AF: 0.000303 AC: 74 AN: 244060 AF XY: 0.000362

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 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

African (AFR) AF: 0.000121 AC: 4 AN: 32990

American (AMR) AF: 0.000203 AC: 9 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.000730 AC: 19 AN: 26042

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38972

South Asian (SAS) AF: 0.000780 AC: 67 AN: 85860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1110656

Other (OTH) AF: 0.000365 AC: 22 AN: 60208

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

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.96
PhyloP100		-0.34
PromoterAI		-0.038	Neutral
Mutation Taster		=99/1	polymorphism

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: rs145400180; hg19: chr18-11752564;