chr4-47936479-G-A

Position:

• chr4-47936479-G-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.2003C>T​(p.Thr668Ile) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNGA1 NM_001379270.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

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]

NIPAL1 (HGNC:):

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=0.12206471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGA1	NM_001379270.1	c.2003C>T	p.Thr668Ile	missense_variant	11/11	ENST00000514170.7	NP_001366199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGA1	ENST00000514170.7	c.2003C>T	p.Thr668Ile	missense_variant	11/11	5	NM_001379270.1	ENSP00000426862.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 12, 2021

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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CNGA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 672 of the CNGA1 protein (p.Thr672Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.088	.;T;.;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.69	.;.;T;T;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Uncertain	2.3	.;M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;N;.;N;N
REVEL	Benign	0.19
Sift	Benign	0.082	T;T;.;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.022	.;B;.;B;B
Vest4		0.15
MutPred		0.23		.;Gain of glycosylation at S675 (P = 0.0409);.;Gain of glycosylation at S675 (P = 0.0409);Gain of glycosylation at S675 (P = 0.0409);
MVP		0.92
MPC		0.12
ClinPred		0.20	T
GERP RS		2.8
Varity_R		0.042
gMVP		0.13

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

Other links and lift over

dbSNP: rs763662167; hg19: chr4-47938496;