rs11926958

Variant names:

• chr3-121808979-A-G
• rs11926958
• NM_001023570.4:c.424T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001023570.4(IQCB1):​c.424T>C​(p.Phe142Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00187 in 1,608,856 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: IQCB1 NM_001023570.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.26
• Publications: 7 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=0.006232977).
• BP6: Variant 3-121808979-A-G is Benign according to our data. Variant chr3-121808979-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219982.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 = 0.0102 (1557/152020) while in subpopulation AFR AF = 0.035 (1454/41564). AF 95% confidence interval is 0.0335. There are 19 homozygotes in GnomAd4. There are 693 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

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.424T>C	p.Phe142Leu	missense	Exon 6 of 15	NP_001018864.2	Q15051-1
	IQCB1	NM_001319107.2		c.424T>C	p.Phe142Leu	missense	Exon 6 of 15	NP_001306036.1	Q15051-1
	IQCB1	NM_001023571.4		c.424T>C	p.Phe142Leu	missense	Exon 6 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.424T>C	p.Phe142Leu	missense	Exon 6 of 15	ENSP00000311505.6	Q15051-1
	IQCB1	ENST00000349820.10	TSL:1	c.424T>C	p.Phe142Leu	missense	Exon 6 of 12	ENSP00000323756.7	Q15051-2
	IQCB1	ENST00000923631.1		c.496T>C	p.Phe166Leu	missense	Exon 7 of 16	ENSP00000593690.1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 151902 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000885

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00269 AC: 675 AN: 250804 AF XY: 0.00206

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.00100 AC: 1458 AN: 1456836 Hom.: 25 Cov.: 29 AF XY: 0.000863 AC XY: 626 AN XY: 724998

African (AFR) AF: 0.0369 AC: 1228 AN: 33322

American (AMR) AF: 0.00155 AC: 69 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5752

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1107840

Other (OTH) AF: 0.00189 AC: 114 AN: 60192

GnomAD4 genome AF: 0.0102 AC: 1557 AN: 152020 Hom.: 19 Cov.: 32 AF XY: 0.00932 AC XY: 693 AN XY: 74320

African (AFR) AF: 0.0350 AC: 1454 AN: 41564

American (AMR) AF: 0.00471 AC: 72 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000885 AC: 6 AN: 67792

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00322 Hom.: 33

Bravo AF: 0.0119

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00320 AC: 389

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.84
MutPred		0.24		Loss of loop (P = 0.0153)
MVP		0.57
MPC		0.34
ClinPred		0.048	T
GERP RS		5.5
Varity_R		0.34
gMVP		0.60
Mutation Taster		=66/34	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: rs11926958; hg19: chr3-121527826; COSMIC: COSV99051693;