Genetic Variant NM_001023570.4:c.588T>C (chr3-121799374-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001023570.4(IQCB1):c.588T>C(p.Ser196Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,540,662 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 6 hom. )

Consequence

IQCB1
NM_001023570.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0003364

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.65

Publications

3 publications found

Variant links:

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

IQCB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 3-121799374-A-G is Benign according to our data. Variant chr3-121799374-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.64 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0025 (379/151854) while in subpopulation AFR AF = 0.0086 (357/41516). AF 95% confidence interval is 0.00786. There are 1 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQCB1	NM_001023570.4	MANE Select	c.588T>C	p.Ser196Ser	splice_region synonymous	Exon 8 of 15	NP_001018864.2	Q15051-1
IQCB1	NM_001319107.2		c.588T>C	p.Ser196Ser	splice_region synonymous	Exon 8 of 15	NP_001306036.1	Q15051-1
IQCB1	NM_001023571.4		c.587+7970T>C		intron	N/A	NP_001018865.2	Q15051-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQCB1	ENST00000310864.11	TSL:1 MANE Select	c.588T>C	p.Ser196Ser	splice_region synonymous	Exon 8 of 15	ENSP00000311505.6	Q15051-1
IQCB1	ENST00000349820.10	TSL:1	c.587+7970T>C		intron	N/A	ENSP00000323756.7	Q15051-2
IQCB1	ENST00000923631.1		c.660T>C	p.Ser220Ser	splice_region synonymous	Exon 9 of 16	ENSP00000593690.1

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

378

AN:

151736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00860

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000592

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000745

AC:

173

AN:

232228

AF XY:

0.000523

show subpopulations

Gnomad AFR exome

AF:

0.00922

Gnomad AMR exome

AF:

0.000735

Gnomad ASJ exome

AF:

0.000947

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000680

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000371

AC:

515

AN:

1388808

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

227

AN XY:

694052

show subpopulations

African (AFR)

AF:

0.0101

AC:

321

AN:

31680

American (AMR)

AF:

0.000788

AC:

AN:

43146

Ashkenazi Jewish (ASJ)

AF:

0.000910

AC:

AN:

25286

East Asian (EAS)

AF:

0.00

AC:

AN:

39142

South Asian (SAS)

AF:

0.00

AC:

AN:

83226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.00178

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.0000657

AC:

AN:

1050186

Other (OTH)

AF:

0.00100

AC:

AN:

57726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00250

AC:

379

AN:

151854

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

188

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.00860

AC:

357

AN:

41516

American (AMR)

AF:

0.000591

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000591

AC:

AN:

67716

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00272

Asia WGS

AF:

0.00145

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Nephronophthisis (1)

Senior-Loken syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.45

PhyloP100

1.6

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00034

dbscSNV1_RF

Benign

0.028

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over