19-55455329-T-G

Variant names:

• chr19-55455329-T-G
• NM_001136201.2:c.350A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001136201.2(ISOC2):​c.350A>C​(p.Asn117Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ISOC2 NM_001136201.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.636

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32330894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC2	NM_001136201.2	c.350A>C	p.Asn117Thr	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000425675.7	NP_001129673.1
ISOC2	NM_024710.3	c.398A>C	p.Asn133Thr	missense_variant	Exon 4 of 6		NP_078986.1
ISOC2	XM_047439445.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 3 of 5		XP_047295401.1
ISOC2	NM_001136202.2	c.140A>C	p.Asn47Thr	missense_variant, splice_region_variant	Exon 3 of 5		NP_001129674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC2	ENST00000425675.7	c.350A>C	p.Asn117Thr	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_001136201.2	ENSP00000401726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.398A>C (p.N133T) alteration is located in exon 4 (coding exon 3) of the ISOC2 gene. This alteration results from a A to C substitution at nucleotide position 398, causing the asparagine (N) at amino acid position 133 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	0.31
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.10	.;T;.;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.33	T;D;T;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.040	D;T;T;.;.
Sift4G	Benign	0.29	T;T;T;.;.
Polyphen		0.59	P;B;B;.;.
Vest4		0.36
MutPred		0.73		.;Loss of loop (P = 0.0603);.;Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);
MVP		0.36
MPC		0.13
ClinPred		0.19	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.40

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: chr19-55966696;