1-109608722-C-T

Position:

• chr1-109608722-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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 Likely benign (★★).

• 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:7
• Conservation: PhyloP100: 2.02

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 -20 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 [Likely_benign]. Clinvar id is 197251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAT2	NM_001377295.2	c.370G>A	p.Val124Met	missense_variant	5/9	ENST00000679935.1	NP_001364224.1
GNAT2	NM_001379232.1	c.370G>A	p.Val124Met	missense_variant	5/9		NP_001366161.1
GNAT2	NM_005272.5	c.370G>A	p.Val124Met	missense_variant	4/8		NP_005263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAT2	ENST00000679935.1	c.370G>A	p.Val124Met	missense_variant	5/9		NM_001377295.2	ENSP00000505083	P1
GNAT2	ENST00000351050.8	c.370G>A	p.Val124Met	missense_variant	4/8	1		ENSP00000251337	P1
GNAT2	ENST00000622865.1	c.370G>A	p.Ter124=	incomplete_terminal_codon_variant, coding_sequence_variant	5/5	3		ENSP00000482596

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

GnomAD3 exomes AF: 0.00515 AC: 1295 AN: 251464 Hom.: 1 AF XY: 0.00547 AC XY: 744 AN XY: 135904

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 SAS exome AF: 0.00578

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

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00608

Gnomad4 FIN exome AF: 0.00417

Gnomad4 NFE exome AF: 0.00785

Gnomad4 OTH exome AF: 0.00666

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

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00706

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00505 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GNAT2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Achromatopsia 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 11, 2014

- -

GNAT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.87	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs41280330; hg19: chr1-110151344; COSMIC: COSV63555135;