rs17849995

Variant names:

• chr3-121781852-C-T
• rs17849995
• NM_001023570.4:c.1301G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:9
• Conservation: PhyloP100: 3.90
• Publications: 35 publications found

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]

IQCB1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Senior-Loken syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001023570.4. 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
	IQCB1	NM_001023570.4	MANE Select	c.1301G>A	p.Cys434Tyr	missense	Exon 13 of 15	NP_001018864.2	Q15051-1
	IQCB1	NM_001319107.2		c.1301G>A	p.Cys434Tyr	missense	Exon 13 of 15	NP_001306036.1	Q15051-1
	IQCB1	NM_001023571.4		c.902G>A	p.Cys301Tyr	missense	Exon 10 of 12	NP_001018865.2	Q15051-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQCB1	ENST00000310864.11	TSL:1 MANE Select	c.1301G>A	p.Cys434Tyr	missense	Exon 13 of 15	ENSP00000311505.6	Q15051-1
	IQCB1	ENST00000349820.10	TSL:1	c.902G>A	p.Cys301Tyr	missense	Exon 10 of 12	ENSP00000323756.7	Q15051-2
	IQCB1	ENST00000923631.1		c.1373G>A	p.Cys458Tyr	missense	Exon 14 of 16	ENSP00000593690.1

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

GnomAD2 exomes AF: 0.300 AC: 75379 AN: 251354 AF XY: 0.295

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 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

African (AFR) AF: 0.229 AC: 7669 AN: 33452

American (AMR) AF: 0.556 AC: 24852 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5965 AN: 26110

East Asian (EAS) AF: 0.160 AC: 6331 AN: 39636

South Asian (SAS) AF: 0.389 AC: 33529 AN: 86226

European-Finnish (FIN) AF: 0.246 AC: 13141 AN: 53336

Middle Eastern (MID) AF: 0.236 AC: 1359 AN: 5762

European-Non Finnish (NFE) AF: 0.239 AC: 264984 AN: 1110910

Other (OTH) AF: 0.255 AC: 15356 AN: 60318

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

African (AFR) AF: 0.235 AC: 9742 AN: 41432

American (AMR) AF: 0.431 AC: 6573 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3466

East Asian (EAS) AF: 0.167 AC: 864 AN: 5170

South Asian (SAS) AF: 0.405 AC: 1943 AN: 4796

European-Finnish (FIN) AF: 0.248 AC: 2609 AN: 10540

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16129 AN: 67944

Other (OTH) AF: 0.266 AC: 561 AN: 2110

Alfa AF: 0.248 Hom.: 9221

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Senior-Loken syndrome 5 (3)
-	-	2	not provided (2)
-	-	1	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.20
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.83	P
Vest4		0.24
MPC		0.40
ClinPred		0.025	T
GERP RS		3.7
Varity_R		0.12
gMVP		0.40
Mutation Taster		=86/14	polymorphism (auto)

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