1-109603486-A-G

Position:

• chr1-109603486-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001377295.2(GNAT2):​c.933T>C​(p.Asn311=) 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

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 Benign. Variant got -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 id is 198818.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAT2	NM_001377295.2	c.933T>C	p.Asn311=	synonymous_variant	9/9	ENST00000679935.1
GNAT2	NM_001379232.1	c.933T>C	p.Asn311=	synonymous_variant	9/9
GNAT2	NM_005272.5	c.933T>C	p.Asn311=	synonymous_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAT2	ENST00000679935.1	c.933T>C	p.Asn311=	synonymous_variant	9/9		NM_001377295.2	P1
GNAT2	ENST00000351050.8	c.933T>C	p.Asn311=	synonymous_variant	8/8	1		P1

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

GnomAD3 exomes AF: 0.00535 AC: 1344 AN: 251368 Hom.: 8 AF XY: 0.00520 AC XY: 706 AN XY: 135848

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 SAS exome AF: 0.00170

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

Gnomad4 AFR exome AF: 0.000869

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.00651

Gnomad4 OTH exome AF: 0.00452

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

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.00711

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00541 Hom.: 3

Bravo AF: 0.00356

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Achromatopsia 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 12, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.6
DANN	Benign	0.73

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: rs34723289; hg19: chr1-110146108;