rs2170646

Variant names:

• chr4-155696940-G-A
• rs2170646
• NM_001130682.3:c.73G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-155696940-G-A
• chr4-155696940-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130682.3(GUCY1A1):​c.73G>A​(p.Val25Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,613,388 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (230 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (203 hom.)
• Consequence: GUCY1A1 NM_001130682.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.77
• Publications: 9 publications found

Genes affected

GUCY1A1 (HGNC:4685): (guanylate cyclase 1 soluble subunit alpha 1) 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. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

GUCY1A1 Gene-Disease associations (from GenCC):

• Moyamoya disease with early-onset achalasia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015866458).
• BP6: Variant 4-155696940-G-A is Benign according to our data. Variant chr4-155696940-G-A is described in ClinVar as Benign. ClinVar VariationId is 715600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130682.3. 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
	GUCY1A1	NM_001130682.3	MANE Select	c.73G>A	p.Val25Ile	missense	Exon 3 of 10	NP_001124154.1	Q02108-1
	GUCY1A1	NM_000856.6		c.73G>A	p.Val25Ile	missense	Exon 4 of 11	NP_000847.2	Q02108-1
	GUCY1A1	NM_001130683.4		c.73G>A	p.Val25Ile	missense	Exon 3 of 10	NP_001124155.1	Q02108-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A1	ENST00000506455.6	TSL:1 MANE Select	c.73G>A	p.Val25Ile	missense	Exon 3 of 10	ENSP00000424361.1	Q02108-1
	GUCY1A1	ENST00000296518.11	TSL:1	c.73G>A	p.Val25Ile	missense	Exon 3 of 10	ENSP00000296518.7	Q02108-1
	GUCY1A1	ENST00000511108.5	TSL:1	c.73G>A	p.Val25Ile	missense	Exon 4 of 11	ENSP00000421493.1	Q02108-1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4505 AN: 152130 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00782 AC: 1961 AN: 250876 AF XY: 0.00589

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00632

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00304 AC: 4449 AN: 1461140 Hom.: 203 Cov.: 30 AF XY: 0.00269 AC XY: 1952 AN XY: 726942

African (AFR) AF: 0.100 AC: 3346 AN: 33450

American (AMR) AF: 0.00692 AC: 309 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5764

European-Non Finnish (NFE) AF: 0.000265 AC: 295 AN: 1111400

Other (OTH) AF: 0.00686 AC: 414 AN: 60374

GnomAD4 genome AF: 0.0297 AC: 4529 AN: 152248 Hom.: 230 Cov.: 33 AF XY: 0.0290 AC XY: 2160 AN XY: 74454

African (AFR) AF: 0.102 AC: 4235 AN: 41526

American (AMR) AF: 0.0138 AC: 211 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0106 Hom.: 172

Bravo AF: 0.0332

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0944 AC: 416

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00921 AC: 1118

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.21
Sift	Benign	0.34	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.015
MVP		0.78
MPC		0.062
ClinPred		0.010	T
GERP RS		5.9
Varity_R		0.057
gMVP		0.15
Mutation Taster		=298/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2170646; hg19: chr4-156618092;