2-98370049-T-C

Position:

• chr2-98370049-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001298.3(CNGA3):​c.74T>C​(p.Leu25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CNGA3 NM_001298.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11950937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA3	NM_001298.3	c.74T>C	p.Leu25Pro	missense_variant	2/8	ENST00000272602.7	NP_001289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGA3	ENST00000272602.7	c.74T>C	p.Leu25Pro	missense_variant	2/8	1	NM_001298.3	ENSP00000272602.2
CNGA3	ENST00000436404.6	c.74T>C	p.Leu25Pro	missense_variant	2/7	1		ENSP00000410070.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461538 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727028

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: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

CNGA3: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	13
DANN	Benign	0.60
DEOGEN2	Benign	0.13	T;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.57	T;T;.
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0040	B;.;B
Vest4		0.24
MutPred		0.30		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.93
MPC		0.17
ClinPred		0.090	T
GERP RS		3.0
Varity_R		0.37
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1692251065; hg19: chr2-98986512;