19-55455077-C-A

Variant names:

• chr19-55455077-C-A
• rs551380020
• NM_001136201.2:c.449G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001136201.2(ISOC2):​c.449G>T​(p.Arg150Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000405 in 1,234,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: ISOC2 NM_001136201.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136201.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISOC2	NM_001136201.2	MANE Select	c.449G>T	p.Arg150Leu	missense	Exon 5 of 6	NP_001129673.1	Q96AB3-1
	ISOC2	NM_024710.3		c.497G>T	p.Arg166Leu	missense	Exon 5 of 6	NP_078986.1	Q96AB3-2
	ISOC2	NM_001136202.2		c.239G>T	p.Arg80Leu	missense	Exon 4 of 5	NP_001129674.1	Q96AB3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISOC2	ENST00000425675.7	TSL:1 MANE Select	c.449G>T	p.Arg150Leu	missense	Exon 5 of 6	ENSP00000401726.1	Q96AB3-1
	ISOC2	ENST00000085068.7	TSL:2	c.497G>T	p.Arg166Leu	missense	Exon 5 of 6	ENSP00000085068.2	Q96AB3-2
	ISOC2	ENST00000910877.1		c.497G>T	p.Arg166Leu	missense	Exon 6 of 7	ENSP00000580936.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000405 AC: 5 AN: 1234848 Hom.: 0 Cov.: 35 AF XY: 0.00000653 AC XY: 4 AN XY: 612740

African (AFR) AF: 0.00 AC: 0 AN: 27894

American (AMR) AF: 0.00 AC: 0 AN: 38308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18052

East Asian (EAS) AF: 0.0000512 AC: 1 AN: 19548

South Asian (SAS) AF: 0.00 AC: 0 AN: 83720

European-Finnish (FIN) AF: 0.0000301 AC: 1 AN: 33230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4572

European-Non Finnish (NFE) AF: 0.00000311 AC: 3 AN: 963482

Other (OTH) AF: 0.00 AC: 0 AN: 46042

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.68		Loss of MoRF binding (P = 0.0305)
MVP		0.56
MPC		0.48
ClinPred		0.95	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.76
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs551380020; hg19: chr19-55966444;