19-55455276-C-A

Variant names:

• chr19-55455276-C-A
• rs763865471
• NM_001136201.2:c.403G>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.403G>T​(p.Ala135Ser) 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. 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. A135T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ISOC2 NM_001136201.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• 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, 0.821

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.403G>T	p.Ala135Ser	missense	Exon 4 of 6	NP_001129673.1	Q96AB3-1
	ISOC2	NM_024710.3		c.451G>T	p.Ala151Ser	missense	Exon 4 of 6	NP_078986.1	Q96AB3-2
	ISOC2	NM_001136202.2		c.193G>T	p.Ala65Ser	missense	Exon 3 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.403G>T	p.Ala135Ser	missense	Exon 4 of 6	ENSP00000401726.1	Q96AB3-1
	ISOC2	ENST00000085068.7	TSL:2	c.451G>T	p.Ala151Ser	missense	Exon 4 of 6	ENSP00000085068.2	Q96AB3-2
	ISOC2	ENST00000910877.1		c.451G>T	p.Ala151Ser	missense	Exon 5 of 7	ENSP00000580936.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		1.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.015	D
Polyphen		0.77	P
Vest4		0.38
MutPred		0.80		Gain of disorder (P = 0.0166)
MVP		0.52
MPC		0.17
ClinPred		0.98	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.088
gMVP		0.68
Mutation Taster		=80/20	polymorphism

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: rs763865471; hg19: chr19-55966643;