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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001136201.2(ISOC2):c.449G>A(p.Arg150His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,378,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ISOC2
NM_001136201.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC2	NM_001136201.2 link	c.449G>A	p.Arg150His	missense_variant	Exon 5 of 6	ENST00000425675.7	NP_001129673.1	Q96AB3-1
ISOC2	NM_024710.3 link	c.497G>A	p.Arg166His	missense_variant	Exon 5 of 6		NP_078986.1	Q96AB3-2
ISOC2	NM_001136202.2 link	c.239G>A	p.Arg80His	missense_variant	Exon 4 of 5		NP_001129674.1	Q96AB3-3
ISOC2	XM_047439445.1 link	c.287G>A	p.Arg96His	missense_variant	Exon 4 of 5		XP_047295401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC2	ENST00000425675.7 link	c.449G>A	p.Arg150His	missense_variant	Exon 5 of 6	1	NM_001136201.2	ENSP00000401726.1		Q96AB3-1

Frequencies

GnomAD3 genomes

AF:

0.0000559

AC:

AN:

143084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000746

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000687

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000618

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000807

AC:

AN:

247782

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000718

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000858

AC:

106

AN:

1234846

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

612738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000339

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000861

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000559

AC:

AN:

143228

Hom.:

Cov.:

AF XY:

0.0000430

AC XY:

AN XY:

69724

show subpopulations

Gnomad4 AFR

AF:

0.0000745

Gnomad4 AMR

AF:

0.0000685

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000618

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497G>A (p.R166H) alteration is located in exon 5 (coding exon 4) of the ISOC2 gene. This alteration results from a G to A substitution at nucleotide position 497, causing the arginine (R) at amino acid position 166 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

.;T;.;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.68

D;D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.5

.;H;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.5

D;D;D;.;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D;D;.;.

Sift4G

Uncertain

0.0020

D;D;D;.;.

Polyphen

1.0

D;D;D;.;.

Vest4

0.80

MutPred

0.63

.;Loss of MoRF binding (P = 0.0289);.;Loss of MoRF binding (P = 0.0289);Loss of MoRF binding (P = 0.0289);

MVP

0.65

MPC

0.25

ClinPred

0.94

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.68

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over