6-42155586-G-T

Position:

• chr6-42155586-G-T

Variant summary

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

The NM_001319061.2(GUCA1ANB-GUCA1A):​c.-836G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 717,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: GUCA1ANB-GUCA1A NM_001319061.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.586

Genes affected

GUCA1ANB-GUCA1A (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=0.006054044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1ANB-GUCA1A	NM_001319061.2	c.-836G>T		5_prime_UTR_variant	1/6		NP_001305990.1
GUCA1ANB	NM_001384994.1	c.9+101G>T		intron_variant		ENST00000623004.2	NP_001371923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIMIP3	ENST00000623004.2	c.9+101G>T		intron_variant		3	NM_001384994.1	ENSP00000485219	P1
CIMIP3	ENST00000372963.4	c.47G>T	p.Gly16Val	missense_variant	1/2	2		ENSP00000362054

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000477 AC: 72 AN: 151036 Hom.: 0 AF XY: 0.000444 AC XY: 36 AN XY: 81158

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00548

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000432 AC: 244 AN: 565238 Hom.: 1 Cov.: 0 AF XY: 0.000436 AC XY: 133 AN XY: 304994

Gnomad4 AFR exome AF: 0.000506

Gnomad4 AMR exome AF: 0.0000288

Gnomad4 ASJ exome AF: 0.00649

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.0000626

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74438

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000564 AC: 14

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	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.62
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.89	D;D;D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.018
Sift	Benign	0.040	D
Sift4G	Uncertain	0.056	T
Vest4		0.27
MVP		0.29
ClinPred		0.043	T
GERP RS		-0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs181327724; hg19: chr6-42123324;