3-121770439-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001023570.4(IQCB1):c.1703T>C(p.Leu568Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000269 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.57

Genes affected

IQCB1 (HGNC:28949): (IQ motif containing B1) This gene encodes a nephrocystin protein that interacts with calmodulin and the retinitis pigmentosa GTPase regulator protein. The encoded protein has a central coiled-coil region and two calmodulin-binding IQ domains. It is localized to the primary cilia of renal epithelial cells and connecting cilia of photoreceptor cells. The protein is thought to play a role in ciliary function. Defects in this gene result in Senior-Loken syndrome type 5. Alternative splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0652425).
• BP6: Variant 3-121770439-A-G is Benign according to our data. Variant chr3-121770439-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 695529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00131 (200/152308) while in subpopulation AFR AF= 0.00467 (194/41560). AF 95% confidence interval is 0.00413. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCB1	NM_001023570.4	c.1703T>C	p.Leu568Pro	missense_variant	15/15	ENST00000310864.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCB1	ENST00000310864.11	c.1703T>C	p.Leu568Pro	missense_variant	15/15	1	NM_001023570.4	P1
IQCB1	ENST00000349820.10	c.1304T>C	p.Leu435Pro	missense_variant	12/12	1
IQCB1	ENST00000393650.7	c.*681T>C		3_prime_UTR_variant, NMD_transcript_variant	14/14	5

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000362 AC: 91 AN: 251422 Hom.: 2 AF XY: 0.000258 AC XY: 35 AN XY: 135888

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727246

Gnomad4 AFR exome AF: 0.00591

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74472

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000343 Hom.: 2

Bravo AF: 0.00179

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

IQCB1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.065	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;D
Vest4		0.92
MVP		0.96
MPC		0.52
ClinPred		0.10	T
GERP RS		5.5
Varity_R		0.86
gMVP		0.77

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: rs145400780; hg19: chr3-121489286;