11-106776446-G-T

Variant summary

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

The NM_000855.3(GUCY1A2):c.1829C>A(p.Pro610Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GUCY1A2 NM_000855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49

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]

LOC112268081 (HGNC:):

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=0.41547436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY1A2	NM_000855.3	c.1829C>A	p.Pro610Gln	missense_variant	6/8	ENST00000526355.7
LOC112268081	XR_002957264.2	n.485+272G>T		intron_variant, non_coding_transcript_variant
GUCY1A2	NM_001256424.2	c.1829C>A	p.Pro610Gln	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY1A2	ENST00000526355.7	c.1829C>A	p.Pro610Gln	missense_variant	6/8	1	NM_000855.3	P1
GUCY1A2	ENST00000282249.6	c.1829C>A	p.Pro610Gln	missense_variant	6/9	1
GUCY1A2	ENST00000347596.2	c.1892C>A	p.Pro631Gln	missense_variant	7/9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250822 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460412 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726610

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: 0.0000144

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Jan 06, 2023

The c.1829C>A (p.P610Q) alteration is located in exon 6 (coding exon 6) of the GUCY1A2 gene. This alteration results from a C to A substitution at nucleotide position 1829, causing the proline (P) at amino acid position 610 to be replaced by a glutamine (Q). 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	0.18
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;T;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.55
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.94	P;B;.
Vest4		0.55
MutPred		0.50		Gain of MoRF binding (P = 0.0671);Gain of MoRF binding (P = 0.0671);.;
MVP		0.89
MPC		0.66
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.89

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: rs781424682; hg19: chr11-106647172; COSMIC: COSV56505175;