19-55455376-G-C

Variant names:

• chr19-55455376-G-C
• NM_001136201.2:c.349-46C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024710.3(ISOC2):​c.351C>G​(p.Asp117Glu) 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. 13/17 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_024710.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14062524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC2	NM_001136201.2	c.349-46C>G		intron_variant	Intron 3 of 5	ENST00000425675.7	NP_001129673.1
ISOC2	NM_024710.3	c.351C>G	p.Asp117Glu	missense_variant, splice_region_variant	Exon 4 of 6		NP_078986.1
ISOC2	XM_047439445.1	c.141C>G	p.Asp47Glu	missense_variant, splice_region_variant	Exon 3 of 5		XP_047295401.1
ISOC2	NM_001136202.2	c.139-46C>G		intron_variant	Intron 2 of 4		NP_001129674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC2	ENST00000425675.7	c.349-46C>G		intron_variant	Intron 3 of 5	1	NM_001136201.2	ENSP00000401726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.351C>G (p.D117E) alteration is located in exon 4 (coding exon 3) of the ISOC2 gene. This alteration results from a C to G substitution at nucleotide position 351, causing the aspartic acid (D) at amino acid position 117 to be replaced by a glutamic acid (E). 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
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.3
DANN	Benign	0.91
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.052	T
Polyphen		0.020	B
Vest4		0.14
MutPred		0.71		Gain of glycosylation at P122 (P = 0.1363);
MVP		0.45
MPC		0.073
ClinPred		0.12	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-55966743;