rs370118361

Variant names:

• chr18-11689815-G-A
• rs370118361
• NM_182978.4:c.252G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-11689815-G-A
• chr18-11689815-G-C

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_182978.4(GNAL):​c.252G>A​(p.Glu84Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,537,772 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: GNAL NM_182978.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.28
• 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: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 18-11689815-G-A is Benign according to our data. Variant chr18-11689815-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1175112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00181 (275/152088) while in subpopulation AMR AF = 0.00347 (53/15276). AF 95% confidence interval is 0.00272. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 275 AD gene.

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.252G>A	p.Glu84Glu	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.252G>A	p.Glu84Glu	synonymous	Exon 1 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000585590.1	TSL:2	n.126G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 151980 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00179 AC: 253 AN: 141000 AF XY: 0.00201

Gnomad AFR exome AF: 0.000414

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00243 AC: 3364 AN: 1385684 Hom.: 9 Cov.: 32 AF XY: 0.00245 AC XY: 1679 AN XY: 685442

African (AFR) AF: 0.000309 AC: 9 AN: 29104

American (AMR) AF: 0.00158 AC: 57 AN: 36156

Ashkenazi Jewish (ASJ) AF: 0.000774 AC: 19 AN: 24558

East Asian (EAS) AF: 0.00 AC: 0 AN: 33058

South Asian (SAS) AF: 0.00326 AC: 255 AN: 78280

European-Finnish (FIN) AF: 0.000136 AC: 6 AN: 44160

Middle Eastern (MID) AF: 0.00248 AC: 14 AN: 5640

European-Non Finnish (NFE) AF: 0.00266 AC: 2869 AN: 1077222

Other (OTH) AF: 0.00235 AC: 135 AN: 57506

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152088 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74358

African (AFR) AF: 0.000530 AC: 22 AN: 41524

American (AMR) AF: 0.00347 AC: 53 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.00260 AC: 177 AN: 67958

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00195 Hom.: 2

Bravo AF: 0.00181

Asia WGS AF: 0.00146 AC: 5 AN: 3430

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Dystonic disorder (1)
-	-	1	GNAL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Uncertain	0.98
PhyloP100		1.3
Mutation Taster		=95/5	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs370118361; hg19: chr18-11689814; COSMIC: COSV61849190;