chr16-56334777-C-T

Variant names:

• chr16-56334777-C-T
• rs1065375
• NM_020988.3:c.513C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020988.3(GNAO1):​c.513C>T​(p.Thr171Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,613,306 control chromosomes in the GnomAD database, including 136,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14308 hom., cov: 34)
  • Exomes 𝑓: 0.40 (122114 hom.)
• Consequence: GNAO1 NM_020988.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.914
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-56334777-C-T is Benign according to our data. Variant chr16-56334777-C-T is described in ClinVar as Benign. ClinVar VariationId is 585942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAO1	NM_020988.3	c.513C>T	p.Thr171Thr	synonymous_variant	Exon 5 of 9	ENST00000262493.12	NP_066268.1
GNAO1	NM_138736.3	c.513C>T	p.Thr171Thr	synonymous_variant	Exon 5 of 8		NP_620073.2
GNAO1	XM_011523003.4	c.387C>T	p.Thr129Thr	synonymous_variant	Exon 5 of 9		XP_011521305.1
GNAO1	XR_007064866.1	n.1260C>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAO1	ENST00000262493.12	c.513C>T	p.Thr171Thr	synonymous_variant	Exon 5 of 9	1	NM_020988.3	ENSP00000262493.6

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64632 AN: 152010 Hom.: 14285 Cov.: 34

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.437

GnomAD2 exomes AF: 0.444 AC: 111505 AN: 251174 AF XY: 0.437

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.758

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.394

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.402 AC: 587225 AN: 1461178 Hom.: 122114 Cov.: 37 AF XY: 0.401 AC XY: 291271 AN XY: 726928

African (AFR) AF: 0.404 AC: 13521 AN: 33470

American (AMR) AF: 0.515 AC: 23014 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 10682 AN: 26126

East Asian (EAS) AF: 0.776 AC: 30822 AN: 39694

South Asian (SAS) AF: 0.363 AC: 31314 AN: 86242

European-Finnish (FIN) AF: 0.480 AC: 25561 AN: 53272

Middle Eastern (MID) AF: 0.388 AC: 2238 AN: 5766

European-Non Finnish (NFE) AF: 0.382 AC: 424657 AN: 1111522

Other (OTH) AF: 0.421 AC: 25416 AN: 60370

GnomAD4 genome AF: 0.425 AC: 64702 AN: 152128 Hom.: 14308 Cov.: 34 AF XY: 0.434 AC XY: 32245 AN XY: 74380

African (AFR) AF: 0.411 AC: 17047 AN: 41490

American (AMR) AF: 0.497 AC: 7604 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1396 AN: 3472

East Asian (EAS) AF: 0.752 AC: 3883 AN: 5166

South Asian (SAS) AF: 0.391 AC: 1888 AN: 4824

European-Finnish (FIN) AF: 0.489 AC: 5185 AN: 10596

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26313 AN: 67968

Other (OTH) AF: 0.442 AC: 935 AN: 2116

Alfa AF: 0.405 Hom.: 35253

Bravo AF: 0.428

Asia WGS AF: 0.583 AC: 2028 AN: 3478

EpiCase AF: 0.398

EpiControl AF: 0.403

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 73. Only high quality variants are reported. -

Inborn genetic diseases Benign:1

Feb 09, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 17 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder with involuntary movements Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.3
DANN	Benign	0.88
PhyloP100		-0.91
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1065375; hg19: chr16-56368689;