Genetic Variant NM_153208.3:c.245C>A (chr16-19730493-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153208.3(IQCK):c.245C>A(p.Thr82Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T82R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IQCK
NM_153208.3 missense, splice_region

Scores

Splicing: ADA: 0.0005339

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0870

Publications

0 publications found

Variant links:

Genes affected

IQCK (HGNC:28556): (IQ motif containing K) This gene belongs to the IQ motif-containing family of proteins. The IQ motif serves as a binding site for different EF-hand proteins such as calmodulin. This gene was identified as a potential candidate gene for obsessive-compulsive disorder in a genome-wide association study. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

IQCK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.111888945).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQCK	NM_153208.3	MANE Select	c.245C>A	p.Thr82Lys	missense splice_region	Exon 2 of 9	NP_694940.1	Q8N0W5-1
IQCK	NM_001394804.1		c.245C>A	p.Thr82Lys	missense splice_region	Exon 2 of 10	NP_001381733.1	Q8N0W5-1
IQCK	NM_001394806.1		c.245C>A	p.Thr82Lys	missense splice_region	Exon 2 of 8	NP_001381735.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQCK	ENST00000695302.1	MANE Select	c.245C>A	p.Thr82Lys	missense splice_region	Exon 2 of 9	ENSP00000511791.1	Q8N0W5-1
IQCK	ENST00000320394.10	TSL:1	c.245C>A	p.Thr82Lys	missense splice_region	Exon 3 of 10	ENSP00000324901.6	Q8N0W5-1
IQCK	ENST00000308214.13	TSL:1	n.245C>A		splice_region non_coding_transcript_exon	Exon 3 of 8	ENSP00000309261.9	Q8N0W5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33202

American (AMR)

AF:

0.00

AC:

AN:

43700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39418

South Asian (SAS)

AF:

0.00

AC:

AN:

84550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106894

Other (OTH)

AF:

0.00

AC:

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.8

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0039

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.49

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

0.087

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

REVEL

Benign

0.031

Sift

Benign

0.28

Sift4G

Benign

0.12

Polyphen

0.65

Vest4

0.25

MutPred

0.41

Gain of methylation at T82 (P = 0.004)

MVP

0.22

MPC

0.56

ClinPred

0.20

GERP RS

2.5

Varity_R

0.10

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00053

dbscSNV1_RF

Benign

0.11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over