6-42162989-C-A

Variant names:

• chr6-42162989-C-A
• rs886061391
• NM_001384994.1:c.79C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384994.1(CIMIP3):​c.79C>A​(p.His27Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 714,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CIMIP3 NM_001384994.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.87
• Publications: 0 publications found

Genes affected

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]

GUCA1ANB-GUCA1A (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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068306655).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384994.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIMIP3	NM_001384994.1	MANE Select	c.79C>A	p.His27Asn	missense	Exon 2 of 2	NP_001371923.1	X6R8D5-1
	CIMIP3	NM_001370581.1		c.124C>A	p.His42Asn	missense	Exon 2 of 2	NP_001357510.1	X6R8D5-2
	GUCA1ANB-GUCA1A	NM_000409.5		c.-388C>A		5_prime_UTR	Exon 2 of 6	NP_000400.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIMIP3	ENST00000623004.2	TSL:3 MANE Select	c.79C>A	p.His27Asn	missense	Exon 2 of 2	ENSP00000485219.1	X6R8D5-1
	GUCA1ANB-GUCA1A	ENST00000654459.1		c.-282+7396C>A		intron	N/A	ENSP00000499539.1
	CIMIP3	ENST00000372963.4	TSL:2	c.124C>A	p.His42Asn	missense	Exon 2 of 2	ENSP00000362054.3	X6R8D5-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000134 AC: 2 AN: 149240 AF XY: 0.0000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000142 AC: 8 AN: 562310 Hom.: 0 Cov.: 0 AF XY: 0.00000989 AC XY: 3 AN XY: 303302

African (AFR) AF: 0.00 AC: 0 AN: 15732

American (AMR) AF: 0.00 AC: 0 AN: 34506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19836

East Asian (EAS) AF: 0.00 AC: 0 AN: 32014

South Asian (SAS) AF: 0.0000963 AC: 6 AN: 62320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 315406

Other (OTH) AF: 0.0000654 AC: 2 AN: 30580

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cone dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.024
DANN	Benign	0.63
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.98	T
PhyloP100		-2.9
REVEL	Benign	0.0060
Sift4G	Benign	0.40	T
Vest4		0.14
MVP		0.030
ClinPred		0.032	T
GERP RS		-0.51
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs886061391; hg19: chr6-42130727;