18-11752499-C-T

Variant names:

• chr18-11752499-C-T
• rs73397885
• NM_001369387.1:c.66C>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.66C>T​(p.Arg22Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,612,980 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R22R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0093 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (46 hom.)
• Consequence: GNAL NM_001369387.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.307
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 18-11752499-C-T is Benign according to our data. Variant chr18-11752499-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.307 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00928 (1414/152298) while in subpopulation AFR AF = 0.0169 (703/41566). AF 95% confidence interval is 0.0159. There are 10 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1414 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	NM_001369387.1	MANE Plus Clinical	c.66C>T	p.Arg22Arg	synonymous	Exon 1 of 12	NP_001356316.1
	GNAL	NM_182978.4	MANE Select	c.377-354C>T		intron	N/A	NP_892023.1
	GNAL	NM_001142339.3		c.66C>T	p.Arg22Arg	synonymous	Exon 2 of 13	NP_001135811.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.66C>T	p.Arg22Arg	synonymous	Exon 1 of 12	ENSP00000408489.2
	GNAL	ENST00000535121.5	TSL:1	c.66C>T	p.Arg22Arg	synonymous	Exon 2 of 13	ENSP00000439023.1
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.377-354C>T		intron	N/A	ENSP00000334051.5

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152180 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00554 AC: 1380 AN: 248982 AF XY: 0.00548

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00640

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00569 AC: 8309 AN: 1460682 Hom.: 46 Cov.: 31 AF XY: 0.00571 AC XY: 4147 AN XY: 726664

African (AFR) AF: 0.0169 AC: 564 AN: 33336

American (AMR) AF: 0.00664 AC: 296 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00299 AC: 258 AN: 86148

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53408

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5766

European-Non Finnish (NFE) AF: 0.00598 AC: 6652 AN: 1111494

Other (OTH) AF: 0.00625 AC: 377 AN: 60344

GnomAD4 genome AF: 0.00928 AC: 1414 AN: 152298 Hom.: 10 Cov.: 33 AF XY: 0.00948 AC XY: 706 AN XY: 74472

African (AFR) AF: 0.0169 AC: 703 AN: 41566

American (AMR) AF: 0.00914 AC: 140 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00628 AC: 427 AN: 68024

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00749 Hom.: 6

Bravo AF: 0.0108

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00807

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dystonic disorder Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GNAL-related disorder Benign:1

Mar 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.96
PhyloP100		0.31
PromoterAI		-0.028	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73397885; hg19: chr18-11752498;