1-109603452-T-C

Variant names:

• chr1-109603452-T-C
• rs1476110210
• NM_001377295.2:c.967A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001377295.2(GNAT2):​c.967A>G​(p.Met323Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,596,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GNAT2 NM_001377295.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.967A>G	p.Met323Val	missense_variant	Exon 9 of 9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1	c.967A>G	p.Met323Val	missense_variant	Exon 9 of 9		NP_001366161.1
GNAT2	NM_005272.5	c.967A>G	p.Met323Val	missense_variant	Exon 8 of 8		NP_005263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.967A>G	p.Met323Val	missense_variant	Exon 9 of 9		NM_001377295.2	ENSP00000505083.1
GNAT2	ENST00000351050.8	c.967A>G	p.Met323Val	missense_variant	Exon 8 of 8	1		ENSP00000251337.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444412 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 719848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.967A>G (p.M323V) alteration is located in exon 8 (coding exon 8) of the GNAT2 gene. This alteration results from a A to G substitution at nucleotide position 967, causing the methionine (M) at amino acid position 323 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.0078
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.89	L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.43
Sift	Benign	0.054	T
Sift4G	Benign	0.085	T
Polyphen		0.20	B
Vest4		0.67
MutPred		0.60		Loss of catalytic residue at M323 (P = 0.0125);
MVP		0.89
MPC		0.46
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.42
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs1476110210; hg19: chr1-110146074;