rs6804162

Variant names:

• chr3-108920537-T-C
• rs6804162
• NM_005459.4:c.253A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M85R) has been classified as Uncertain significance.

• 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005459.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1C	NM_005459.4	MANE Select	c.253A>G	p.Met85Val	missense	Exon 2 of 4	NP_005450.3
	GUCA1C	NM_001363884.1		c.253A>G	p.Met85Val	missense	Exon 2 of 4	NP_001350813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1C	ENST00000261047.8	TSL:1 MANE Select	c.253A>G	p.Met85Val	missense	Exon 2 of 4	ENSP00000261047.3
	GUCA1C	ENST00000393963.7	TSL:1	c.253A>G	p.Met85Val	missense	Exon 2 of 4	ENSP00000377535.3
	GUCA1C	ENST00000471108.1	TSL:2	c.253A>G	p.Met85Val	missense	Exon 2 of 3	ENSP00000417761.1

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

GnomAD2 exomes AF: 0.337 AC: 84246 AN: 250090 AF XY: 0.338

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 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

African (AFR) AF: 0.395 AC: 12745 AN: 32246

American (AMR) AF: 0.227 AC: 10096 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 8943 AN: 25758

East Asian (EAS) AF: 0.243 AC: 9590 AN: 39446

South Asian (SAS) AF: 0.293 AC: 24978 AN: 85138

European-Finnish (FIN) AF: 0.483 AC: 25745 AN: 53336

Middle Eastern (MID) AF: 0.307 AC: 1660 AN: 5408

European-Non Finnish (NFE) AF: 0.351 AC: 372718 AN: 1062442

Other (OTH) AF: 0.346 AC: 20226 AN: 58516

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

African (AFR) AF: 0.408 AC: 16914 AN: 41472

American (AMR) AF: 0.281 AC: 4295 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1274 AN: 3470

East Asian (EAS) AF: 0.244 AC: 1263 AN: 5178

South Asian (SAS) AF: 0.301 AC: 1452 AN: 4816

European-Finnish (FIN) AF: 0.489 AC: 5160 AN: 10558

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24927 AN: 67954

Other (OTH) AF: 0.336 AC: 709 AN: 2108

Alfa AF: 0.360 Hom.: 29748

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 v4.9

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
MetaRNN	Benign	0.00023	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.71	N
PhyloP100		-0.024
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.057
Sift	Benign	0.52	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.028
ClinPred		0.0015	T
GERP RS		3.1
Varity_R		0.16
gMVP		0.26
Mutation Taster		=100/0	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: rs6804162; hg19: chr3-108639384; COSMIC: COSV53754359;