1-109608722-C-T

Variant names:

• chr1-109608722-C-T
• rs41280330
• NM_001377295.2:c.370G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001377295.2(GNAT2):​c.370G>A​(p.Val124Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,613,258 control chromosomes in the GnomAD database, including 48 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 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (44 hom.)
• Consequence: GNAT2 NM_001377295.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.02
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008829892).
• BP6: Variant 1-109608722-C-T is Benign according to our data. Variant chr1-109608722-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197251.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00437 (665/152288) while in subpopulation SAS AF = 0.00746 (36/4824). AF 95% confidence interval is 0.00653. There are 4 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.370G>A	p.Val124Met	missense	Exon 5 of 9	NP_001364224.1	P19087
	GNAT2	NM_001379232.1		c.370G>A	p.Val124Met	missense	Exon 5 of 9	NP_001366161.1	Q5T697
	GNAT2	NM_005272.5		c.370G>A	p.Val124Met	missense	Exon 4 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.370G>A	p.Val124Met	missense	Exon 5 of 9	ENSP00000505083.1	P19087
	GNAT2	ENST00000351050.8	TSL:1	c.370G>A	p.Val124Met	missense	Exon 4 of 8	ENSP00000251337.3	P19087
	GNAT2	ENST00000872462.1		c.370G>A	p.Val124Met	missense	Exon 5 of 10	ENSP00000542521.1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00706

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00515 AC: 1295 AN: 251464 AF XY: 0.00547

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.00758

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00694 AC: 10137 AN: 1460970 Hom.: 44 Cov.: 30 AF XY: 0.00692 AC XY: 5029 AN XY: 726862

African (AFR) AF: 0.00102 AC: 34 AN: 33464

American (AMR) AF: 0.00224 AC: 100 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00608 AC: 524 AN: 86236

European-Finnish (FIN) AF: 0.00417 AC: 223 AN: 53420

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.00785 AC: 8726 AN: 1111174

Other (OTH) AF: 0.00666 AC: 402 AN: 60364

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74468

African (AFR) AF: 0.00120 AC: 50 AN: 41564

American (AMR) AF: 0.00320 AC: 49 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4824

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00706 AC: 480 AN: 68026

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00471 Hom.: 1

Bravo AF: 0.00416

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00544 AC: 661

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00605

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Achromatopsia 4 (3)
-	-	3	not provided (3)
-	-	1	GNAT2-related disorder (1)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.34
Sift	Benign	0.046	D
Sift4G	Benign	0.065	T
Polyphen		0.99	D
Vest4		0.43
MVP		0.92
MPC		0.35
ClinPred		0.049	T
GERP RS		4.7
Varity_R		0.20
gMVP		0.81
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41280330; hg19: chr1-110151344; COSMIC: COSV63555135;