rs767982659

Variant names:

• chr11-106708540-G-A
• rs767982659
• NM_000855.3:c.1963C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-106708540-G-A
• chr11-106708540-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000855.3(GUCY1A2):​c.1963C>T​(p.Arg655Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R655S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GUCY1A2 NM_000855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A2	NM_000855.3	MANE Select	c.1963C>T	p.Arg655Cys	missense	Exon 7 of 8	NP_000846.1	P33402-1
	GUCY1A2	NM_001256424.2		c.2056C>T	p.Arg686Cys	missense	Exon 8 of 9	NP_001243353.1	P33402-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A2	ENST00000526355.7	TSL:1 MANE Select	c.1963C>T	p.Arg655Cys	missense	Exon 7 of 8	ENSP00000431245.2	P33402-1
	GUCY1A2	ENST00000282249.6	TSL:1	c.2056C>T	p.Arg686Cys	missense	Exon 8 of 9	ENSP00000282249.2	P33402-2
	GUCY1A2	ENST00000347596.2	TSL:1	c.2026C>T	p.Arg676Cys	missense	Exon 8 of 9	ENSP00000344874.2	P33402-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249644 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460274 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726444

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111018

Other (OTH) AF: 0.00 AC: 0 AN: 60324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000896614), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000596

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.9	M
PhyloP100		4.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.41
Sift	Benign	0.081	T
Sift4G	Benign	0.15	T
Polyphen		0.14	B
Vest4		0.40
MutPred		0.70		Loss of disorder (P = 0.0165)
MVP		0.77
MPC		0.86
ClinPred		0.50	T
GERP RS		6.0
Varity_R		0.25
gMVP		0.61
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767982659; hg19: chr11-106579266; COSMIC: COSV56478103;