rs41289504

Variant names:

• chr18-11881003-C-T
• rs41289504
• NM_182978.4:c.1245C>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_182978.4(GNAL):​c.1245C>T​(p.Ala415Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,020 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 32)
  • Exomes 𝑓: 0.013 (138 hom.)
• Consequence: GNAL NM_182978.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.657
• Publications: 5 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=-0.35).
• BP6: Variant 18-11881003-C-T is Benign according to our data. Variant chr18-11881003-C-T is described in ClinVar as Benign. ClinVar VariationId is 416012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.657 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00805 (1226/152320) while in subpopulation NFE AF = 0.0132 (898/68028). AF 95% confidence interval is 0.0125. There are 12 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1226 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.1245C>T	p.Ala415Ala	synonymous	Exon 12 of 12	NP_892023.1
	GNAL	NM_001369387.1	MANE Plus Clinical	c.1014C>T	p.Ala338Ala	synonymous	Exon 12 of 12	NP_001356316.1
	GNAL	NM_001142339.3		c.1014C>T	p.Ala338Ala	synonymous	Exon 13 of 13	NP_001135811.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAL	ENST00000334049.11	TSL:1 MANE Select	c.1245C>T	p.Ala415Ala	synonymous	Exon 12 of 12	ENSP00000334051.5
	GNAL	ENST00000423027.8	TSL:1 MANE Plus Clinical	c.1014C>T	p.Ala338Ala	synonymous	Exon 12 of 12	ENSP00000408489.2
	GNAL	ENST00000535121.5	TSL:1	c.1014C>T	p.Ala338Ala	synonymous	Exon 13 of 13	ENSP00000439023.1

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152202 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00898 AC: 2253 AN: 250938 AF XY: 0.00911

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0132 AC: 19269 AN: 1461700 Hom.: 138 Cov.: 31 AF XY: 0.0129 AC XY: 9353 AN XY: 727152

African (AFR) AF: 0.00254 AC: 85 AN: 33476

American (AMR) AF: 0.00467 AC: 209 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 329 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00399 AC: 344 AN: 86236

European-Finnish (FIN) AF: 0.00631 AC: 337 AN: 53412

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5764

European-Non Finnish (NFE) AF: 0.0156 AC: 17327 AN: 1111900

Other (OTH) AF: 0.00952 AC: 575 AN: 60380

GnomAD4 genome AF: 0.00805 AC: 1226 AN: 152320 Hom.: 12 Cov.: 32 AF XY: 0.00754 AC XY: 562 AN XY: 74490

African (AFR) AF: 0.00231 AC: 96 AN: 41572

American (AMR) AF: 0.00549 AC: 84 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 898 AN: 68028

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0117 Hom.: 6

Bravo AF: 0.00824

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0155

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.5
DANN	Benign	0.92
PhyloP100		-0.66
Mutation Taster		=100/0	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: rs41289504; hg19: chr18-11881002; COSMIC: COSV99304439; COSMIC: COSV99304439;