1-109606352-C-T

Position:

• chr1-109606352-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001377295.2(GNAT2):​c.546G>A​(p.Thr182Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,609,972 control chromosomes in the GnomAD database, including 162,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T182T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (12575 hom., cov: 32)
  • Exomes 𝑓: 0.45 (149456 hom.)
• Consequence: GNAT2 NM_001377295.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.20

Genes affected

GNAT2 (HGNC:4394): (G protein subunit alpha transducin 2) Transducin is a 3-subunit guanine nucleotide-binding protein (G protein) which stimulates the coupling of rhodopsin and cGMP-phoshodiesterase during visual impulses. The transducin alpha subunits in rods and cones are encoded by separate genes. This gene encodes the alpha subunit in cones. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 1-109606352-C-T is Benign according to our data. Variant chr1-109606352-C-T is described in ClinVar as [Benign]. Clinvar id is 259744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-109606352-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.546G>A	p.Thr182Thr	synonymous_variant	6/9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1	c.546G>A	p.Thr182Thr	synonymous_variant	6/9		NP_001366161.1
GNAT2	NM_005272.5	c.546G>A	p.Thr182Thr	synonymous_variant	5/8		NP_005263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.546G>A	p.Thr182Thr	synonymous_variant	6/9		NM_001377295.2	ENSP00000505083.1
GNAT2	ENST00000351050.8	c.546G>A	p.Thr182Thr	synonymous_variant	5/8	1		ENSP00000251337.3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55833 AN: 151818 Hom.: 12562 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.400

GnomAD3 exomes AF: 0.465 AC: 116935 AN: 251492 Hom.: 29393 AF XY: 0.462 AC XY: 62740 AN XY: 135920

Gnomad AFR exome AF: 0.0971

Gnomad AMR exome AF: 0.628

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.641

Gnomad SAS exome AF: 0.401

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.445 AC: 648962 AN: 1458036 Hom.: 149456 Cov.: 31 AF XY: 0.444 AC XY: 322256 AN XY: 725592

Gnomad4 AFR exome AF: 0.0917

Gnomad4 AMR exome AF: 0.614

Gnomad4 ASJ exome AF: 0.438

Gnomad4 EAS exome AF: 0.664

Gnomad4 SAS exome AF: 0.402

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.442

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.368 AC: 55860 AN: 151936 Hom.: 12575 Cov.: 32 AF XY: 0.374 AC XY: 27785 AN XY: 74248

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.635

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.446

Gnomad4 OTH AF: 0.404

Alfa AF: 0.427 Hom.: 24093

Bravo AF: 0.363

Asia WGS AF: 0.481 AC: 1670 AN: 3478

EpiCase AF: 0.448

EpiControl AF: 0.462

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Achromatopsia 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	5.7
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799875; hg19: chr1-110148974; COSMIC: COSV63554552; COSMIC: COSV63554552;