chr16-56328741-A-G

Variant names:

• chr16-56328741-A-G
• rs141057479
• NM_020988.3:c.414A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_020988.3(GNAO1):​c.414A>G​(p.Gln138Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,614,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: GNAO1 NM_020988.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.29
• Publications: 0 publications found

Genes affected

GNAO1 (HGNC:4389): (G protein subunit alpha o1) The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

GNAO1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• movement disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• neurodevelopmental disorder with involuntary movements

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-56328741-A-G is Benign according to our data. Variant chr16-56328741-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.29 with no splicing effect.
• BS2: High AC in GnomAd4 at 82 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020988.3. 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
	GNAO1	NM_020988.3	MANE Select	c.414A>G	p.Gln138Gln	synonymous	Exon 4 of 9	NP_066268.1
	GNAO1	NM_138736.3		c.414A>G	p.Gln138Gln	synonymous	Exon 4 of 8	NP_620073.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAO1	ENST00000262493.12	TSL:1 MANE Select	c.414A>G	p.Gln138Gln	synonymous	Exon 4 of 9	ENSP00000262493.6
	GNAO1	ENST00000262494.13	TSL:1	c.414A>G	p.Gln138Gln	synonymous	Exon 4 of 8	ENSP00000262494.7
	GNAO1	ENST00000638705.1	TSL:1	c.414A>G	p.Gln138Gln	synonymous	Exon 4 of 8	ENSP00000491223.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000664 AC: 167 AN: 251490 AF XY: 0.000670

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000682 AC: 997 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000637 AC XY: 463 AN XY: 727248

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000790 AC: 879 AN: 1112008

Other (OTH) AF: 0.000646 AC: 39 AN: 60396

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74502

African (AFR) AF: 0.000240 AC: 10 AN: 41598

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000808 AC: 55 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000849 Hom.: 0

Bravo AF: 0.000771

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00119

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	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.6
DANN	Benign	0.55
PhyloP100		2.3
PromoterAI		-0.019	Neutral
Mutation Taster		=99/1	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: rs141057479; hg19: chr16-56362653; COSMIC: COSV99341601;