rs17849995

chr3-121781852-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001023570.4(IQCB1):c.1301G>A(p.Cys434Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.256 in 1,612,350 control chromosomes in the GnomAD database, including 57,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5650 hom., cov: 31)
  • Exomes 𝑓: 0.26 (51526 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013995767).
• BP6: Variant 3-121781852-C-T is Benign according to our data. Variant chr3-121781852-C-T is described in ClinVar as [Benign]. Clinvar id is 257090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121781852-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCB1	NM_001023570.4	c.1301G>A	p.Cys434Tyr	missense_variant	13/15	ENST00000310864.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCB1	ENST00000310864.11	c.1301G>A	p.Cys434Tyr	missense_variant	13/15	1	NM_001023570.4	P1
IQCB1	ENST00000349820.10	c.902G>A	p.Cys301Tyr	missense_variant	10/12	1
IQCB1	ENST00000393650.7	c.*279G>A		3_prime_UTR_variant, NMD_transcript_variant	12/14	5

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39381 AN: 151780 Hom.: 5635 Cov.: 31

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.300 AC: 75379 AN: 251354 Hom.: 13516 AF XY: 0.295 AC XY: 40141 AN XY: 135852

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.163

Gnomad SAS exome AF: 0.396

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.256 AC: 373186 AN: 1460450 Hom.: 51526 Cov.: 35 AF XY: 0.258 AC XY: 187809 AN XY: 726566

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.556

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.260 AC: 39429 AN: 151900 Hom.: 5650 Cov.: 31 AF XY: 0.268 AC XY: 19887 AN XY: 74226

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.431

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.405

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.266

Alfa AF: 0.245 Hom.: 5868

Bravo AF: 0.268

TwinsUK AF: 0.248 AC: 920

ALSPAC AF: 0.250 AC: 963

ESP6500AA AF: 0.233 AC: 1026

ESP6500EA AF: 0.239 AC: 2057

ExAC AF: 0.289 AC: 35062

Asia WGS AF: 0.313 AC: 1088 AN: 3478

EpiCase AF: 0.242

EpiControl AF: 0.238

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Senior-Loken syndrome 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Benign	0.82
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.54	P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.20
Sift	Benign	0.16	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.83	P;D
Vest4		0.24
MPC		0.40
ClinPred		0.025	T
GERP RS		3.7
Varity_R		0.12
gMVP		0.40

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: rs17849995; hg19: chr3-121500699; COSMIC: COSV60436034;