NM_001136201.2:c.349-8A>C

Variant names:

• chr19-55455338-T-G
• rs1599881790
• NM_001136201.2:c.349-8A>C

Variant summary

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

The NM_001136201.2(ISOC2):​c.349-8A>C variant causes a splice region, intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ISOC2 NM_001136201.2 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.842

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.349-8A>C		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000425675.7	NP_001129673.1
ISOC2	NM_024710.3	c.389A>C	p.Tyr130Ser	missense_variant	Exon 4 of 6		NP_078986.1
ISOC2	XM_047439445.1	c.179A>C	p.Tyr60Ser	missense_variant	Exon 3 of 5		XP_047295401.1
ISOC2	NM_001136202.2	c.139-8A>C		splice_region_variant, 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.349-8A>C		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_001136201.2	ENSP00000401726.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389A>C (p.Y130S) 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 389, causing the tyrosine (Y) at amino acid position 130 to be replaced by a serine (S). 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	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.67
DANN	Benign	0.56
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.063
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.38		Gain of disorder (P = 0.0076);
MVP		0.27
MPC		0.11
ClinPred		0.17	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 40

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1599881790; hg19: chr19-55966705;