Genetic Variant ISL2:p.Glu148Gln (chr15-76338445-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_145805.3(ISL2):c.442G>C(p.Glu148Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000045 in 1,443,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ISL2
NM_145805.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

Variant links:

Genes affected

ISL2 (HGNC:18524): (ISL LIM homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in axonogenesis; neuron fate specification; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of neuron differentiation and neuron differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ISL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10385138).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISL2	NM_145805.3 link	c.442G>C	p.Glu148Gln	missense_variant	Exon 3 of 6	ENST00000290759.9	NP_665804.1	Q96A47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ISL2	ENST00000290759.9 link	c.442G>C	p.Glu148Gln	missense_variant	Exon 3 of 6	1	NM_145805.3	ENSP00000290759.4	Q96A47
ISL2	ENST00000558437.1 link	n.724G>C		non_coding_transcript_exon_variant	Exon 2 of 2	3
ISL2	ENST00000558656.1 link	n.248+478G>C		intron_variant	Intron 2 of 4	5		ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000978

AC:

AN:

71610

Hom.:

AF XY:

0.0000722

AC XY:

AN XY:

41562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000283

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000346

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000441

AC:

AN:

1291638

Hom.:

Cov.:

AF XY:

0.0000346

AC XY:

AN XY:

636188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000873

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000145

Gnomad4 SAS exome

AF:

0.000161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000367

Gnomad4 OTH exome

AF:

0.0000376

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000218

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442G>C (p.E148Q) alteration is located in exon 3 (coding exon 3) of the ISL2 gene. This alteration results from a G to C substitution at nucleotide position 442, causing the glutamic acid (E) at amino acid position 148 to be replaced by a glutamine (Q). 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

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.19

Eigen

Benign

-0.077

Eigen_PC

Benign

0.066

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.34

MutationAssessor

Benign

2.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Benign

0.27

Sift4G

Benign

0.13

Polyphen

0.012

Vest4

0.24

MutPred

0.30

Gain of MoRF binding (P = 0.2385);

MVP

0.91

MPC

0.77

ClinPred

0.035

GERP RS

4.5

Varity_R

0.26

gMVP

0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over