rs2101121277

Variant names:

• chr1-109603487-T-C
• rs2101121277
• NM_001377295.2:c.932A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001377295.2(GNAT2):​c.932A>G​(p.Asn311Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N311D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAT2 NM_001377295.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

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.932A>G	p.Asn311Ser	missense	Exon 9 of 9	NP_001364224.1	P19087
	GNAT2	NM_001379232.1		c.932A>G	p.Asn311Ser	missense	Exon 9 of 9	NP_001366161.1	Q5T697
	GNAT2	NM_005272.5		c.932A>G	p.Asn311Ser	missense	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.932A>G	p.Asn311Ser	missense	Exon 9 of 9	ENSP00000505083.1	P19087
	GNAT2	ENST00000351050.8	TSL:1	c.932A>G	p.Asn311Ser	missense	Exon 8 of 8	ENSP00000251337.3	P19087
	GNAT2	ENST00000872462.1		c.932A>G	p.Asn311Ser	missense	Exon 9 of 10	ENSP00000542521.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		0.97	D
Vest4		0.85
MutPred		0.68		Gain of disorder (P = 0.055)
MVP		0.96
MPC		0.81
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.76
Mutation Taster		=44/56	disease causing

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: rs2101121277; hg19: chr1-110146109;