chr6-42162912-C-T

Position:

• chr6-42162912-C-T

Variant summary

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

The NM_001384994.1(GUCA1ANB):​c.10-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 614,810 control chromosomes in the GnomAD database, including 1,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.067 (782 hom., cov: 32)
  • Exomes 𝑓: 0.025 (352 hom.)
• Consequence: GUCA1ANB NM_001384994.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003861
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0300

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-42162912-C-T is Benign according to our data. Variant chr6-42162912-C-T is described in ClinVar as [Benign]. Clinvar id is 356686.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-42162912-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1ANB	NM_001384994.1	c.10-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000623004.2	NP_001371923.1
GUCA1ANB-GUCA1A	NM_001319061.2	c.-828-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001305990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIMIP3	ENST00000623004.2	c.10-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3	NM_001384994.1	ENSP00000485219	P1
CIMIP3	ENST00000372963.4	c.55-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000362054

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10202 AN: 152066 Hom.: 781 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0285 AC: 2293 AN: 80556 Hom.: 87 AF XY: 0.0265 AC XY: 1089 AN XY: 41154

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.000414

Gnomad SAS exome AF: 0.0130

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.0252 AC: 11659 AN: 462626 Hom.: 352 Cov.: 0 AF XY: 0.0243 AC XY: 5918 AN XY: 243628

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.000135

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0671 AC: 10218 AN: 152184 Hom.: 782 Cov.: 32 AF XY: 0.0639 AC XY: 4754 AN XY: 74398

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0606

Alfa AF: 0.0205 Hom.: 46

Bravo AF: 0.0744

Asia WGS AF: 0.0170 AC: 59 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.96
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0
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: rs58894089; hg19: chr6-42130650;