rs34723289

Variant names:

• chr1-109603486-A-G
• rs34723289
• NM_001377295.2:c.933T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001377295.2(GNAT2):​c.933T>C​(p.Asn311Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,609,454 control chromosomes in the GnomAD database, including 42 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 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (35 hom.)
• Consequence: GNAT2 NM_001377295.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.87
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-109603486-A-G is Benign according to our data. Variant chr1-109603486-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198818.
• BP7: Synonymous conserved (PhyloP=2.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00499 (761/152356) while in subpopulation NFE AF = 0.00711 (484/68028). AF 95% confidence interval is 0.00659. There are 7 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377295.2. 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.933T>C	p.Asn311Asn	synonymous	Exon 9 of 9	NP_001364224.1	P19087
	GNAT2	NM_001379232.1		c.933T>C	p.Asn311Asn	synonymous	Exon 9 of 9	NP_001366161.1	Q5T697
	GNAT2	NM_005272.5		c.933T>C	p.Asn311Asn	synonymous	Exon 8 of 8	NP_005263.1	P19087

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAT2	ENST00000679935.1	MANE Select	c.933T>C	p.Asn311Asn	synonymous	Exon 9 of 9	ENSP00000505083.1	P19087
	GNAT2	ENST00000351050.8	TSL:1	c.933T>C	p.Asn311Asn	synonymous	Exon 8 of 8	ENSP00000251337.3	P19087
	GNAT2	ENST00000872462.1		c.933T>C	p.Asn311Asn	synonymous	Exon 9 of 10	ENSP00000542521.1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152238 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00711

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00535 AC: 1344 AN: 251368 AF XY: 0.00520

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.00719

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00599 AC: 8732 AN: 1457098 Hom.: 35 Cov.: 28 AF XY: 0.00583 AC XY: 4225 AN XY: 725248

African (AFR) AF: 0.000869 AC: 29 AN: 33380

American (AMR) AF: 0.00174 AC: 78 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86174

European-Finnish (FIN) AF: 0.0173 AC: 924 AN: 53378

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.00651 AC: 7215 AN: 1107690

Other (OTH) AF: 0.00452 AC: 272 AN: 60240

GnomAD4 genome AF: 0.00499 AC: 761 AN: 152356 Hom.: 7 Cov.: 32 AF XY: 0.00498 AC XY: 371 AN XY: 74516

African (AFR) AF: 0.00123 AC: 51 AN: 41582

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00711 AC: 484 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00459 Hom.: 3

Bravo AF: 0.00356

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00486

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.6
DANN	Benign	0.73
PhyloP100		2.9
Mutation Taster		=99/1	polymorphism

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: rs34723289; hg19: chr1-110146108;