6-42155579-A-C

Position:

• chr6-42155579-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001319061.2(GUCA1ANB-GUCA1A):​c.-843A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 717,070 control chromosomes in the GnomAD database, including 181,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (34529 hom., cov: 30)
  • Exomes 𝑓: 0.72 (147135 hom.)
• Consequence: GUCA1ANB-GUCA1A NM_001319061.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.33

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.486182E-7).
• BP6: Variant 6-42155579-A-C is Benign according to our data. Variant chr6-42155579-A-C is described in ClinVar as [Benign]. Clinvar id is 356684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1ANB-GUCA1A	NM_001319061.2	c.-843A>C		5_prime_UTR_variant	1/6		NP_001305990.1
GUCA1ANB	NM_001384994.1	c.9+94A>C		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+94A>C		intron_variant		3	NM_001384994.1	ENSP00000485219	P1
CIMIP3	ENST00000372963.4	c.40A>C	p.Met14Leu	missense_variant	1/2	2		ENSP00000362054

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101346 AN: 151792 Hom.: 34515 Cov.: 30

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.860

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.643

GnomAD3 exomes AF: 0.713 AC: 107778 AN: 151118 Hom.: 38750 AF XY: 0.712 AC XY: 57806 AN XY: 81198

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.719

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.861

Gnomad SAS exome AF: 0.665

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.681

GnomAD4 exome AF: 0.719 AC: 406171 AN: 565162 Hom.: 147135 Cov.: 0 AF XY: 0.718 AC XY: 218889 AN XY: 304952

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.711

Gnomad4 ASJ exome AF: 0.751

Gnomad4 EAS exome AF: 0.847

Gnomad4 SAS exome AF: 0.668

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.668 AC: 101403 AN: 151908 Hom.: 34529 Cov.: 30 AF XY: 0.663 AC XY: 49244 AN XY: 74240

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.657

Gnomad4 ASJ AF: 0.743

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.682

Gnomad4 FIN AF: 0.694

Gnomad4 NFE AF: 0.733

Gnomad4 OTH AF: 0.645

Alfa AF: 0.703 Hom.: 34878

Bravo AF: 0.660

TwinsUK AF: 0.728 AC: 2699

ALSPAC AF: 0.744 AC: 2867

ExAC AF: 0.654 AC: 14117

Asia WGS AF: 0.732 AC: 2542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cone dystrophy 3 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.79
DANN	Benign	0.57
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
REVEL	Benign	0.021
Sift4G	Pathogenic	0.0	D
Vest4		0.048
ClinPred		0.0026	T
GERP RS		-1.1

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: rs1132156; hg19: chr6-42123317;