NM_001136201.2:c.523C>A

Variant names:

• chr19-55455003-G-T
• NM_001136201.2:c.523C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001136201.2(ISOC2):​c.523C>A​(p.Pro175Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ISOC2 NM_001136201.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC2	NM_001136201.2	c.523C>A	p.Pro175Thr	missense_variant	Exon 5 of 6	ENST00000425675.7	NP_001129673.1
ISOC2	NM_024710.3	c.571C>A	p.Pro191Thr	missense_variant	Exon 5 of 6		NP_078986.1
ISOC2	NM_001136202.2	c.313C>A	p.Pro105Thr	missense_variant	Exon 4 of 5		NP_001129674.1
ISOC2	XM_047439445.1	c.361C>A	p.Pro121Thr	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	c.523C>A	p.Pro175Thr	missense_variant	Exon 5 of 6	1	NM_001136201.2	ENSP00000401726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.571C>A (p.P191T) alteration is located in exon 5 (coding exon 4) of the ISOC2 gene. This alteration results from a C to A substitution at nucleotide position 571, causing the proline (P) at amino acid position 191 to be replaced by a threonine (T). 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	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D;D;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	0.0016	D
MutationAssessor	Pathogenic	3.3	.;M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.4	D;D;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.016	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.37
MutPred		0.51		.;Loss of disorder (P = 0.1576);.;Loss of disorder (P = 0.1576);
MVP		0.62
MPC		0.47
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-55966370;