2-98391889-G-A

Position:

chr2-98391889-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000272602.7(CNGA3):c.592G>A(p.Glu198Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,154 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 36 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 27 hom. )

Consequence

CNGA3
ENST00000272602.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.96

Variant links:

Genes affected

CNGA3 (HGNC:2150): (cyclic nucleotide gated channel subunit alpha 3) This gene encodes a member of the cyclic nucleotide-gated cation channel protein family which is required for normal vision and olfactory signal transduction. Mutations in this gene are associated with achromatopsia (rod monochromacy) and color blindness. Two alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

CNGA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000272602.7

BP4

Computational evidence support a benign effect (MetaRNN=0.0031558275).

BP6

Variant 2-98391889-G-A is Benign according to our data. Variant chr2-98391889-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1615/152328) while in subpopulation AFR AF= 0.0356 (1479/41568). AF 95% confidence interval is 0.0341. There are 36 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3 linkuse as main transcript	c.592G>A	p.Glu198Lys	missense_variant	7/8	ENST00000272602.7	NP_001289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGA3	ENST00000272602.7 linkuse as main transcript	c.592G>A	p.Glu198Lys	missense_variant	7/8	1	NM_001298.3	ENSP00000272602	A1	Q16281-1
CNGA3	ENST00000436404.6 linkuse as main transcript	c.538G>A	p.Glu180Lys	missense_variant	6/7	1		ENSP00000410070	P4	Q16281-2
CNGA3	ENST00000409937.1 linkuse as main transcript	n.745G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1609

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0355

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00827

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.00363

AC:

912

AN:

251460

Hom.:

AF XY:

0.00260

AC XY:

354

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0389

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00799

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00155

AC:

2267

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1002

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0377

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0132

Gnomad4 SAS exome

AF:

0.000580

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.00331

GnomAD4 genome

AF:

0.0106

AC:

1615

AN:

152328

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

778

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0356

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00829

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.0125

ESP6500AA

AF:

0.0415

AC:

183

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00462

AC:

561

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2021	- -

Achromatopsia 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Apr 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

D;.;D;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.56

T;T;.;T

MetaRNN

Benign

0.0032

T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.3

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.39

T;T;T;T

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.046

B;.;B;.

Vest4

0.23

MVP

0.85

MPC

0.11

ClinPred

0.0048

GERP RS

4.4

Varity_R

0.047

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over