4-47936431-T-A

Variant summary

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

The NM_001379270.1(CNGA1):c.2051A>T(p.Asp684Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D684N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGA1 NM_001379270.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

Genes affected

CNGA1 (HGNC:2148): (cyclic nucleotide gated channel subunit alpha 1) The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene. [provided by RefSeq, Oct 2019]

LOC101927157 (HGNC:):

NIPAL1 (HGNC:27194): (NIPA like domain containing 1) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2368727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNGA1	NM_001379270.1	c.2051A>T	p.Asp684Val	missense_variant	11/11	ENST00000514170.7
LOC101927157	NR_125879.1	n.478+21727T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNGA1	ENST00000514170.7	c.2051A>T	p.Asp684Val	missense_variant	11/11	5	NM_001379270.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Invitae

Mar 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CNGA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 688 of the CNGA1 protein (p.Asp688Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	0.80	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.97	N;N;.;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		0.39	.;B;.;B;B
Vest4		0.26
MutPred		0.20		.;Gain of sheet (P = 0.0073);.;Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);
MVP		0.80
MPC		0.47
ClinPred		0.75	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-47938448;