NM_001384910.1:c.9C>G

Variant names:

• chr6-42173622-C-G
• NM_001384910.1:c.9C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384910.1(GUCA1A):​c.9C>G​(p.Asn3Lys) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N3N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.170

Genes affected

GUCA1A (HGNC:4678): (guanylate cyclase activator 1A) This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

ENSG00000290147 (HGNC:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39289486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.9C>G	p.Asn3Lys	missense_variant	Exon 1 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.9C>G	p.Asn3Lys	missense_variant	Exon 3 of 6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.9C>G	p.Asn3Lys	missense_variant	Exon 3 of 6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.9C>G	p.Asn3Lys	missense_variant	Exon 2 of 5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.9C>G	p.Asn3Lys	missense_variant	Exon 1 of 4	1	NM_001384910.1	ENSP00000362049.1
ENSG00000290147	ENST00000654459.1	c.9C>G	p.Asn3Lys	missense_variant	Exon 2 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with lysine at codon 3 of the GUCA1A protein (p.Asn3Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GUCA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1494647). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;T;T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.64	.;.;.;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	.;L;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.61, 0.57, 0.57
MutPred		0.39		Gain of ubiquitination at N3 (P = 0.0104);Gain of ubiquitination at N3 (P = 0.0104);Gain of ubiquitination at N3 (P = 0.0104);Gain of ubiquitination at N3 (P = 0.0104);
MVP		0.73
MPC		0.85
ClinPred		0.86	D
GERP RS		2.2
Varity_R		0.090
gMVP		0.50

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: chr6-42141360;