NM_001377295.2:c.319C>A

Variant names:

• chr1-109608773-G-T
• rs3738766
• NM_001377295.2:c.319C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377295.2(GNAT2):​c.319C>A​(p.Leu107Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,613,600 control chromosomes in the GnomAD database, including 2,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L107V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (238 hom., cov: 32)
  • Exomes 𝑓: 0.036 (2217 hom.)
• Consequence: GNAT2 NM_001377295.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.06
• Publications: 17 publications found

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]

GNAT2 Gene-Disease associations (from GenCC):

• achromatopsia 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• GNAT2-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• achromatopsia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016860664).
• BP6: Variant 1-109608773-G-T is Benign according to our data. Variant chr1-109608773-G-T is described in ClinVar as Benign. ClinVar VariationId is 259743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.319C>A	p.Leu107Ile	missense_variant	Exon 5 of 9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1	c.319C>A	p.Leu107Ile	missense_variant	Exon 5 of 9		NP_001366161.1
GNAT2	NM_005272.5	c.319C>A	p.Leu107Ile	missense_variant	Exon 4 of 8		NP_005263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.319C>A	p.Leu107Ile	missense_variant	Exon 5 of 9		NM_001377295.2	ENSP00000505083.1
GNAT2	ENST00000351050.8	c.319C>A	p.Leu107Ile	missense_variant	Exon 4 of 8	1		ENSP00000251337.3
GNAT2	ENST00000622865.1	c.319C>A	p.Leu107Ile	missense_variant	Exon 5 of 5	3		ENSP00000482596.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4682 AN: 152160 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0504 AC: 12664 AN: 251434 AF XY: 0.0524

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.0378

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0355 AC: 51912 AN: 1461322 Hom.: 2217 Cov.: 30 AF XY: 0.0376 AC XY: 27353 AN XY: 726966

African (AFR) AF: 0.00571 AC: 191 AN: 33474

American (AMR) AF: 0.0300 AC: 1342 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 673 AN: 26132

East Asian (EAS) AF: 0.232 AC: 9206 AN: 39690

South Asian (SAS) AF: 0.109 AC: 9434 AN: 86238

European-Finnish (FIN) AF: 0.0379 AC: 2026 AN: 53410

Middle Eastern (MID) AF: 0.0430 AC: 248 AN: 5768

European-Non Finnish (NFE) AF: 0.0237 AC: 26303 AN: 1111516

Other (OTH) AF: 0.0412 AC: 2489 AN: 60374

GnomAD4 genome AF: 0.0308 AC: 4685 AN: 152278 Hom.: 238 Cov.: 32 AF XY: 0.0341 AC XY: 2536 AN XY: 74456

African (AFR) AF: 0.00577 AC: 240 AN: 41566

American (AMR) AF: 0.0284 AC: 435 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1240 AN: 5170

South Asian (SAS) AF: 0.118 AC: 570 AN: 4816

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0225 AC: 1532 AN: 68020

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.0283 Hom.: 581

Bravo AF: 0.0280

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0235 AC: 202

ExAC AF: 0.0501 AC: 6081

Asia WGS AF: 0.144 AC: 498 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0245

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Achromatopsia 4 Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.70	N;.
PhyloP100		8.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.50	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.063	T;.
Sift4G	Benign	0.37	T;.
Polyphen		1.0	D;.
Vest4		0.24
MPC		0.53
ClinPred		0.078	T
GERP RS		4.5
Varity_R		0.31
gMVP		0.43
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3738766; hg19: chr1-110151395; COSMIC: COSV63554735;