6-42163005-G-A

Position:

• chr6-42163005-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384994.1(GUCA1ANB):​c.95G>A​(p.Arg32Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 716,588 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: GUCA1ANB NM_001384994.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.119

Genes affected

GUCA1ANB (HGNC:):

CIMIP3 (HGNC:55126): (ciliary microtubule inner protein 3) Predicted to enable guanylate cyclase regulator activity. Predicted to be involved in positive regulation of guanylate cyclase activity. Predicted to act upstream of or within phototransduction; regulation of guanylate cyclase activity; and visual perception. Predicted to be located in cone photoreceptor outer segment and photoreceptor inner segment. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017517298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1ANB	NM_001384994.1	c.95G>A	p.Arg32Gln	missense_variant	2/2	ENST00000623004.2	NP_001371923.1
GUCA1ANB-GUCA1A	NM_001319061.2	c.-743G>A		5_prime_UTR_variant	2/6		NP_001305990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIMIP3	ENST00000623004.2	c.95G>A	p.Arg32Gln	missense_variant	2/2	3	NM_001384994.1	ENSP00000485219	P1
CIMIP3	ENST00000372963.4	c.140G>A	p.Arg47Gln	missense_variant	2/2	2		ENSP00000362054

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000377 AC: 57 AN: 151084 Hom.: 0 AF XY: 0.000345 AC XY: 28 AN XY: 81074

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000890

Gnomad FIN exome AF: 0.000297

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000386 AC: 218 AN: 564404 Hom.: 1 Cov.: 0 AF XY: 0.000387 AC XY: 118 AN XY: 304530

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.0000501

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000319

Gnomad4 FIN exome AF: 0.000334

Gnomad4 NFE exome AF: 0.000562

Gnomad4 OTH exome AF: 0.000326

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74330

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.000389

ExAC AF: 0.0000850 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cone dystrophy 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.75
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
REVEL	Benign	0.0060
Sift4G	Benign	0.56	T;T
Vest4		0.080
MVP		0.030
ClinPred		0.0099	T
GERP RS		-6.8

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: rs200816650; hg19: chr6-42130743;