18-11689813-G-GAGGAGCGCGAGGCGGCCA

Position:

• chr18-11689813-G-GAGGAGCGCGAGGCGGCCA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BS1 BS2

The NM_182978.4(GNAL):​c.266_283dupCCAAGGAGCGCGAGGCGG​(p.Ala89_Ala94dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,537,556 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: GNAL NM_182978.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 2.81

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_182978.4.
• BP6: Variant 18-11689813-G-GAGGAGCGCGAGGCGGCCA is Benign according to our data. Variant chr18-11689813-G-GAGGAGCGCGAGGCGGCCA is described in ClinVar as [Likely_benign]. Clinvar id is 1299265.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000513 (78/152110) while in subpopulation SAS AF= 0.00331 (16/4830). AF 95% confidence interval is 0.00208. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAL	NM_182978.4	c.266_283dupCCAAGGAGCGCGAGGCGG	p.Ala89_Ala94dup	disruptive_inframe_insertion	1/12	ENST00000334049.11	NP_892023.1
GNAL	XM_006722324.4	c.266_283dupCCAAGGAGCGCGAGGCGG	p.Ala89_Ala94dup	disruptive_inframe_insertion	1/6		XP_006722387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAL	ENST00000334049.11	c.266_283dupCCAAGGAGCGCGAGGCGG	p.Ala89_Ala94dup	disruptive_inframe_insertion	1/12	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000585590.1	n.140_157dupCCAAGGAGCGCGAGGCGG		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 152002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000574 AC: 80 AN: 139488 Hom.: 1 AF XY: 0.000760 AC XY: 59 AN XY: 77628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00323

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000269

GnomAD4 exome AF: 0.000374 AC: 518 AN: 1385446 Hom.: 1 Cov.: 32 AF XY: 0.000465 AC XY: 319 AN XY: 685340

Gnomad4 AFR exome AF: 0.000515

Gnomad4 AMR exome AF: 0.000360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000908

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.0000680

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000383

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74358

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	GNAL: BS1 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs750891634; hg19: chr18-11689812;