rs2304355

Variant names:

• chr1-109612902-T-C
• rs2304355
• NM_001377295.2:c.-32A>G

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.-32A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,341,660 control chromosomes in the GnomAD database, including 17,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1515 hom., cov: 31)
  • Exomes 𝑓: 0.16 (15716 hom.)
• Consequence: GNAT2 NM_001377295.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.214
• Publications: 29 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 (BayesDel_noAF=-0.72).
• BP6: Variant 1-109612902-T-C is Benign according to our data. Variant chr1-109612902-T-C is described in ClinVar as Benign. ClinVar VariationId is 259742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.-32A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001377295.2	c.-32A>G		5_prime_UTR_variant	Exon 2 of 9	ENST00000679935.1	NP_001364224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.-32A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9		NM_001377295.2	ENSP00000505083.1
GNAT2	ENST00000679935.1	c.-32A>G		5_prime_UTR_variant	Exon 2 of 9		NM_001377295.2	ENSP00000505083.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19984 AN: 152012 Hom.: 1520 Cov.: 31

Gnomad AFR AF: 0.0650

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.153 AC: 38290 AN: 250382 AF XY: 0.156

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.158 AC: 187436 AN: 1189530 Hom.: 15716 Cov.: 17 AF XY: 0.159 AC XY: 96221 AN XY: 605102

African (AFR) AF: 0.0616 AC: 1745 AN: 28336

American (AMR) AF: 0.150 AC: 6677 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5015 AN: 24420

East Asian (EAS) AF: 0.0951 AC: 3657 AN: 38446

South Asian (SAS) AF: 0.194 AC: 15722 AN: 80856

European-Finnish (FIN) AF: 0.149 AC: 7712 AN: 51712

Middle Eastern (MID) AF: 0.127 AC: 664 AN: 5234

European-Non Finnish (NFE) AF: 0.160 AC: 137984 AN: 864602

Other (OTH) AF: 0.160 AC: 8260 AN: 51518

GnomAD4 genome AF: 0.131 AC: 19976 AN: 152130 Hom.: 1515 Cov.: 31 AF XY: 0.132 AC XY: 9810 AN XY: 74386

African (AFR) AF: 0.0649 AC: 2693 AN: 41508

American (AMR) AF: 0.137 AC: 2102 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 713 AN: 3470

East Asian (EAS) AF: 0.108 AC: 559 AN: 5168

South Asian (SAS) AF: 0.198 AC: 957 AN: 4826

European-Finnish (FIN) AF: 0.157 AC: 1664 AN: 10582

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10820 AN: 67964

Other (OTH) AF: 0.139 AC: 294 AN: 2112

Alfa AF: 0.154 Hom.: 3342

Bravo AF: 0.126

Asia WGS AF: 0.151 AC: 526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 4 Benign:2

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.

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.1
DANN	Benign	0.78
PhyloP100		-0.21
PromoterAI		-0.034	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2304355; hg19: chr1-110155524; COSMIC: COSV107411352; COSMIC: COSV107411352;