11-106978674-G-C

Variant summary

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

The NM_000855.3(GUCY1A2):c.432C>G(p.Asn144Lys) 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. 15/21 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: GUCY1A2 NM_000855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

GUCY1A2 (HGNC:4684): (guanylate cyclase 1 soluble subunit alpha 2) Soluble guanylate cyclases are heterodimeric proteins that catalyze the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. The protein encoded by this gene is an alpha subunit of this complex and it interacts with a beta subunit to form the guanylate cyclase enzyme, which is activated by nitric oxide. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

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=0.19566715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY1A2	NM_000855.3	c.432C>G	p.Asn144Lys	missense_variant	3/8	ENST00000526355.7
GUCY1A2	NM_001256424.2	c.432C>G	p.Asn144Lys	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY1A2	ENST00000526355.7	c.432C>G	p.Asn144Lys	missense_variant	3/8	1	NM_000855.3	P1
GUCY1A2	ENST00000282249.6	c.432C>G	p.Asn144Lys	missense_variant	3/9	1
GUCY1A2	ENST00000347596.2	c.432C>G	p.Asn144Lys	missense_variant	3/9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.432C>G (p.N144K) alteration is located in exon 3 (coding exon 3) of the GUCY1A2 gene. This alteration results from a C to G substitution at nucleotide position 432, causing the asparagine (N) at amino acid position 144 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.095	T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.81	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.61	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.21	B;B;.
Vest4		0.21
MutPred		0.57		Gain of ubiquitination at N144 (P = 0.0048);Gain of ubiquitination at N144 (P = 0.0048);Gain of ubiquitination at N144 (P = 0.0048);
MVP		0.75
MPC		0.61
ClinPred		0.34	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.40

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: chr11-106849400;