19-55455009-C-T

Variant names:

• chr19-55455009-C-T
• rs1042477302
• NM_001136201.2:c.517G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136201.2(ISOC2):​c.517G>A​(p.Val173Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ISOC2 NM_001136201.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.159
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090064555).

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.517G>A	p.Val173Ile	missense	Exon 5 of 6	NP_001129673.1	Q96AB3-1
	ISOC2	NM_024710.3		c.565G>A	p.Val189Ile	missense	Exon 5 of 6	NP_078986.1	Q96AB3-2
	ISOC2	NM_001136202.2		c.307G>A	p.Val103Ile	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.517G>A	p.Val173Ile	missense	Exon 5 of 6	ENSP00000401726.1	Q96AB3-1
	ISOC2	ENST00000085068.7	TSL:2	c.565G>A	p.Val189Ile	missense	Exon 5 of 6	ENSP00000085068.2	Q96AB3-2
	ISOC2	ENST00000910877.1		c.565G>A	p.Val189Ile	missense	Exon 6 of 7	ENSP00000580936.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250426 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460866 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 726772

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111586

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000483 AC: 2 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.7
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.029	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.16
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.010
Sift	Benign	0.18	T
Sift4G	Benign	0.16	T
Polyphen		0.15	B
Vest4		0.25
MutPred		0.34		Gain of catalytic residue at V173 (P = 0.0447)
MVP		0.21
MPC		0.068
ClinPred		0.072	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.15
Mutation Taster		=95/5	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: rs1042477302; hg19: chr19-55966376; COSMIC: COSV50035003; COSMIC: COSV50035003;