19-55455296-T-G

Variant names:

• chr19-55455296-T-G
• rs779830218
• NM_001136201.2:c.383A>C

Variant summary

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

The NM_001136201.2(ISOC2):​c.383A>C​(p.Gln128Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 2.34

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 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	c.383A>C	p.Gln128Pro	missense_variant	Exon 4 of 6	ENST00000425675.7	NP_001129673.1
ISOC2	NM_024710.3	c.431A>C	p.Gln144Pro	missense_variant	Exon 4 of 6		NP_078986.1
ISOC2	NM_001136202.2	c.173A>C	p.Gln58Pro	missense_variant	Exon 3 of 5		NP_001129674.1
ISOC2	XM_047439445.1	c.221A>C	p.Gln74Pro	missense_variant	Exon 3 of 5		XP_047295401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC2	ENST00000425675.7	c.383A>C	p.Gln128Pro	missense_variant	Exon 4 of 6	1	NM_001136201.2	ENSP00000401726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.431A>C (p.Q144P) 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 431, causing the glutamine (Q) at amino acid position 144 to be replaced by a proline (P). 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	0.28
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;.;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D;N;D;.;.
REVEL	Benign	0.19
Sift	Benign	0.039	D;D;D;.;.
Sift4G	Benign	0.091	T;T;T;.;.
Polyphen		0.98	D;P;P;.;.
Vest4		0.52
MutPred		0.52		.;Gain of catalytic residue at L127 (P = 0.1611);.;Gain of catalytic residue at L127 (P = 0.1611);Gain of catalytic residue at L127 (P = 0.1611);
MVP		0.45
MPC		0.096
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.42
gMVP		0.81

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

Other links and lift over

dbSNP: rs779830218; hg19: chr19-55966663;