chr6-42162999-G-A

Position:

• chr6-42162999-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.89G>A​(p.Arg30Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 716,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: GUCA1ANB NM_001384994.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

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=0.00547722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1ANB	NM_001384994.1	c.89G>A	p.Arg30Gln	missense_variant	2/2	ENST00000623004.2	NP_001371923.1
GUCA1ANB-GUCA1A	NM_001319061.2	c.-749G>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.89G>A	p.Arg30Gln	missense_variant	2/2	3	NM_001384994.1	ENSP00000485219	P1
CIMIP3	ENST00000372963.4	c.134G>A	p.Arg45Gln	missense_variant	2/2	2		ENSP00000362054

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000531 AC: 80 AN: 150656 Hom.: 0 AF XY: 0.000384 AC XY: 31 AN XY: 80820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.000362

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000466

GnomAD4 exome AF: 0.000248 AC: 140 AN: 563996 Hom.: 0 Cov.: 0 AF XY: 0.000191 AC XY: 58 AN XY: 304304

Gnomad4 AFR exome AF: 0.0000634

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.000502

Gnomad4 EAS exome AF: 0.0000312

Gnomad4 SAS exome AF: 0.0000959

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000537

Gnomad4 OTH exome AF: 0.000196

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74452

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000344

ExAC AF: 0.000127 AC: 3

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 13, 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	0.072
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
REVEL	Benign	0.068
Sift4G	Benign	0.12	T;T
Vest4		0.099
MVP		0.048
ClinPred		0.034	T
GERP RS		3.6

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: rs184851706; hg19: chr6-42130737;