rs6804162

Positions:

• chr3-108920537-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005459.4(GUCA1C):​c.253A>G​(p.Met85Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,558,878 control chromosomes in the GnomAD database, including 97,424 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (10786 hom., cov: 32)
  • Exomes 𝑓: 0.35 (86638 hom.)
• Consequence: GUCA1C NM_005459.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240

Genes affected

GUCA1C (HGNC:4680): (guanylate cyclase activator 1C) Predicted to enable calcium ion binding activity and calcium sensitive guanylate cyclase activator activity. Predicted to be involved in signal transduction. Predicted to be located in photoreceptor disc membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3213029E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1C	NM_005459.4	c.253A>G	p.Met85Val	missense_variant	2/4	ENST00000261047.8	NP_005450.3
GUCA1C	XM_011513334.3	c.1A>G	p.Met1?	start_lost	2/4		XP_011511636.1
GUCA1C	NM_001363884.1	c.253A>G	p.Met85Val	missense_variant	2/4		NP_001350813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCA1C	ENST00000261047.8	c.253A>G	p.Met85Val	missense_variant	2/4	1	NM_005459.4	ENSP00000261047	P1
GUCA1C	ENST00000393963.7	c.253A>G	p.Met85Val	missense_variant	2/4	1		ENSP00000377535
GUCA1C	ENST00000471108.1	c.253A>G	p.Met85Val	missense_variant	2/3	2		ENSP00000417761

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56412 AN: 151904 Hom.: 10774 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.339

GnomAD3 exomes AF: 0.337 AC: 84246 AN: 250090 Hom.: 15080 AF XY: 0.338 AC XY: 45734 AN XY: 135202

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.222

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.346 AC: 486701 AN: 1406854 Hom.: 86638 Cov.: 26 AF XY: 0.345 AC XY: 242581 AN XY: 703312

Gnomad4 AFR exome AF: 0.395

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.347

Gnomad4 EAS exome AF: 0.243

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.371 AC: 56454 AN: 152024 Hom.: 10786 Cov.: 32 AF XY: 0.372 AC XY: 27637 AN XY: 74302

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.367

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.489

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.336

Alfa AF: 0.359 Hom.: 21222

Bravo AF: 0.358

TwinsUK AF: 0.364 AC: 1351

ALSPAC AF: 0.373 AC: 1439

ESP6500AA AF: 0.419 AC: 1844

ESP6500EA AF: 0.356 AC: 3062

ExAC AF: 0.341 AC: 41429

Asia WGS AF: 0.295 AC: 1025 AN: 3472

EpiCase AF: 0.363

EpiControl AF: 0.350

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.9
DANN	Benign	0.82
DEOGEN2	Benign	0.0054	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.12	T;T;T
MetaRNN	Benign	0.00023	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.71	.;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.012
MPC		0.028
ClinPred		0.0015	T
GERP RS		3.1
Varity_R		0.16
gMVP		0.26

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: rs6804162; hg19: chr3-108639384; COSMIC: COSV53754359;