chr18-11689670-C-CGGCCCT

Variant names:

• chr18-11689670-C-CGGCCCT
• rs201898548
• NM_182978.4:c.113_118dupTGGCCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_182978.4(GNAL):​c.113_118dupTGGCCC​(p.Leu38_Ala39dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,440,082 control chromosomes in the GnomAD database, including 16,271 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1561 hom., cov: 30)
  • Exomes 𝑓: 0.15 (14710 hom.)
• Consequence: GNAL NM_182978.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.750
• Publications: 6 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_182978.4
• BP6: Variant 18-11689670-C-CGGCCCT is Benign according to our data. Variant chr18-11689670-C-CGGCCCT is described in ClinVar as Benign. ClinVar VariationId is 1169619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

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.113_118dupTGGCCC	p.Leu38_Ala39dup	disruptive_inframe_insertion	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.113_118dupTGGCCC	p.Leu38_Ala39dup	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000334051.5	P38405-2
	GNAL	ENST00000585590.1	TSL:2	n.-20_-19insGGCCCT		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21159 AN: 151802 Hom.: 1561 Cov.: 30

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0209

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.0842 AC: 5269 AN: 62574 AF XY: 0.0857

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.00412

Gnomad FIN exome AF: 0.0895

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.0844

GnomAD4 exome AF: 0.146 AC: 188021 AN: 1288172 Hom.: 14710 Cov.: 31 AF XY: 0.144 AC XY: 91635 AN XY: 634178

African (AFR) AF: 0.145 AC: 3750 AN: 25788

American (AMR) AF: 0.0781 AC: 1733 AN: 22180

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 3373 AN: 21518

East Asian (EAS) AF: 0.0319 AC: 888 AN: 27800

South Asian (SAS) AF: 0.0855 AC: 5779 AN: 67576

European-Finnish (FIN) AF: 0.116 AC: 3828 AN: 32866

Middle Eastern (MID) AF: 0.138 AC: 562 AN: 4064

European-Non Finnish (NFE) AF: 0.156 AC: 160955 AN: 1033354

Other (OTH) AF: 0.135 AC: 7153 AN: 53026

GnomAD4 genome AF: 0.139 AC: 21162 AN: 151910 Hom.: 1561 Cov.: 30 AF XY: 0.136 AC XY: 10099 AN XY: 74286

African (AFR) AF: 0.146 AC: 6058 AN: 41492

American (AMR) AF: 0.116 AC: 1765 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3464

East Asian (EAS) AF: 0.0210 AC: 108 AN: 5146

South Asian (SAS) AF: 0.0810 AC: 391 AN: 4830

European-Finnish (FIN) AF: 0.117 AC: 1227 AN: 10514

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10519 AN: 67882

Other (OTH) AF: 0.155 AC: 327 AN: 2110

Alfa AF: 0.0409 Hom.: 39

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.75
Mutation Taster		=71/29	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs201898548; hg19: chr18-11689669; COSMIC: COSV61848978; COSMIC: COSV61848978;