Genetic Variant NM_001136201.2:c.449G>C (chr19-55455077-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001136201.2(ISOC2):c.449G>C(p.Arg150Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000081 in 1,234,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R150C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

ISOC2
NM_001136201.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

Genes affected

ISOC2 (HGNC:26278): (isochorismatase domain containing 2) Involved in protein destabilization. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ISOC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136201.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISOC2	NM_001136201.2	MANE Select	c.449G>C	p.Arg150Pro	missense	Exon 5 of 6	NP_001129673.1	Q96AB3-1
ISOC2	NM_024710.3		c.497G>C	p.Arg166Pro	missense	Exon 5 of 6	NP_078986.1	Q96AB3-2
ISOC2	NM_001136202.2		c.239G>C	p.Arg80Pro	missense	Exon 4 of 5	NP_001129674.1	Q96AB3-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISOC2	ENST00000425675.7	TSL:1 MANE Select	c.449G>C	p.Arg150Pro	missense	Exon 5 of 6	ENSP00000401726.1	Q96AB3-1
ISOC2	ENST00000085068.7	TSL:2	c.497G>C	p.Arg166Pro	missense	Exon 5 of 6	ENSP00000085068.2	Q96AB3-2
ISOC2	ENST00000910877.1		c.497G>C	p.Arg166Pro	missense	Exon 6 of 7	ENSP00000580936.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.10e-7

AC:

AN:

1234848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

612740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27894

American (AMR)

AF:

0.00

AC:

AN:

38308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18052

East Asian (EAS)

AF:

0.00

AC:

AN:

19548

South Asian (SAS)

AF:

0.00

AC:

AN:

83720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4572

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

963482

Other (OTH)

AF:

0.00

AC:

AN:

46042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.1

PhyloP100

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.89

MutPred

0.66

Loss of MoRF binding (P = 0.0099)

MVP

0.74

MPC

0.52

ClinPred

1.0

GERP RS

4.0

Varity_R

0.92

gMVP

0.89

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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