rs104893616

chr2-98396042-C-Gchr2-98396042-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001298.3(CNGA3):c.872C>G(p.Thr291Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNGA3 NM_001298.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Extracellular (size 28) in uniprot entity CNGA3_HUMAN there are 39 pathogenic changes around while only 0 benign (100%) in NM_001298.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 2-98396042-C-G is Pathogenic according to our data. Variant chr2-98396042-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9477.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-98396042-C-G is described in Lovd as [Likely_pathogenic]. Variant chr2-98396042-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA3	NM_001298.3	c.872C>G	p.Thr291Arg	missense_variant	8/8	ENST00000272602.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA3	ENST00000272602.7	c.872C>G	p.Thr291Arg	missense_variant	8/8	1	NM_001298.3	A1
CNGA3	ENST00000436404.6	c.818C>G	p.Thr273Arg	missense_variant	7/7	1		P4
CNGA3	ENST00000409937.1	n.1025C>G		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Achromatopsia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		0.90	P;.;P;.
Vest4		0.92
MVP		1.0
MPC		0.54
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104893616; hg19: chr2-99012505;