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_005272.5(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_005272.5 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAT2	NM_001377295.2	MANE Select	c.-32A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001364224.1
	GNAT2	NM_001377295.2	MANE Select	c.-32A>G		5_prime_UTR	Exon 2 of 9	NP_001364224.1
	GNAT2	NM_001379232.1		c.-32A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001366161.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAT2	ENST00000679935.1	MANE Select	c.-32A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000505083.1
	GNAT2	ENST00000351050.8	TSL:1	c.-32A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000251337.3
	GNAT2	ENST00000679935.1	MANE Select	c.-32A>G		5_prime_UTR	Exon 2 of 9	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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Achromatopsia 4 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;