6-42155585-G-A

Position:

• chr6-42155585-G-A

Variant summary

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

The NM_001370581.1(CIMIP3):​c.46G>A​(p.Gly16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 717,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: CIMIP3 NM_001370581.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.617

Genes affected

ENSG00000290147 (HGNC:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

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=0.0058692396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIMIP3	NM_001384994.1	c.9+100G>A		intron_variant		ENST00000623004.2	NP_001371923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000290147	ENST00000654459	c.-290G>A		5_prime_UTR_variant	1/5			ENSP00000499539.1
GUCA1ANB	ENST00000623004.2	c.9+100G>A		intron_variant		3	NM_001384994.1	ENSP00000485219.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000338 AC: 51 AN: 151026 Hom.: 0 AF XY: 0.000357 AC XY: 29 AN XY: 81152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000570

Gnomad ASJ exome AF: 0.00167

Gnomad EAS exome AF: 0.000464

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000313 AC: 177 AN: 565230 Hom.: 1 Cov.: 0 AF XY: 0.000292 AC XY: 89 AN XY: 304984

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.000461

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.000343

Gnomad4 SAS exome AF: 0.0000319

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.000521

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.000403 AC XY: 30 AN XY: 74436

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000425 Hom.: 0

Bravo AF: 0.000419

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000446 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.6
DANN	Benign	0.68
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.023
Sift	Benign	0.29	T
Sift4G	Benign	0.17	T
Vest4		0.12
MVP		0.030
ClinPred		0.021	T
GERP RS		-1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs188911829; hg19: chr6-42123323;