1-109608722-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001377295.2(GNAT2):c.370G>A(p.Val124Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,613,258 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 44 hom. )

Consequence

GNAT2
NM_001377295.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.02

Publications

8 publications found

Variant links:

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

GNAT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008829892).

BP6

Variant 1-109608722-C-T is Benign according to our data. Variant chr1-109608722-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197251.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00437 (665/152288) while in subpopulation SAS AF = 0.00746 (36/4824). AF 95% confidence interval is 0.00653. There are 4 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAT2	NM_001377295.2 link	c.370G>A	p.Val124Met	missense_variant	Exon 5 of 9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1 link	c.370G>A	p.Val124Met	missense_variant	Exon 5 of 9		NP_001366161.1
GNAT2	NM_005272.5 link	c.370G>A	p.Val124Met	missense_variant	Exon 4 of 8		NP_005263.1	P19087Q5T697

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNAT2	ENST00000679935.1 link	c.370G>A	p.Val124Met	missense_variant	Exon 5 of 9		NM_001377295.2	ENSP00000505083.1	P19087
GNAT2	ENST00000351050.8 link	c.370G>A	p.Val124Met	missense_variant	Exon 4 of 8	1		ENSP00000251337.3	P19087
GNAT2	ENST00000622865.1 link	c.370G>A	p.???124???	splice_region_variant, synonymous_variant	Exon 5 of 5	3		ENSP00000482596.1	A0A087WZE5

Frequencies

GnomAD3 genomes

AF:

0.00438

AC:

666

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00706

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00515

AC:

1295

AN:

251464

AF XY:

0.00547

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.00758

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00694

AC:

10137

AN:

1460970

Hom.:

Cov.:

AF XY:

0.00692

AC XY:

5029

AN XY:

726862

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33464

American (AMR)

AF:

0.00224

AC:

100

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00608

AC:

524

AN:

86236

European-Finnish (FIN)

AF:

0.00417

AC:

223

AN:

53420

Middle Eastern (MID)

AF:

0.00589

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00785

AC:

8726

AN:

1111174

Other (OTH)

AF:

0.00666

AC:

402

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

551

1102

1654

2205

2756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00437

AC:

665

AN:

152288

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41564

American (AMR)

AF:

0.00320

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00746

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00706

AC:

480

AN:

68026

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00471

Hom.:

Bravo

AF:

0.00416

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00544

AC:

661

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00791

EpiControl

AF:

0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GNAT2: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Achromatopsia 4

Benign:3

Jun 30, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 11, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GNAT2-related disorder

Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.045

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

1.6

PhyloP100

2.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.41

REVEL

Uncertain

0.34

Sift

Benign

0.046

Sift4G

Benign

0.065

Polyphen

0.99

Vest4

0.43

MVP

0.92

MPC

0.35

ClinPred

0.049

GERP RS

4.7

Varity_R

0.20

gMVP

0.81

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over