Genetic Variant ISL2:p.Leu146Val (chr15-76338439-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_145805.3(ISL2):c.436C>G(p.Leu146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,458,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ISL2
NM_145805.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

Publications

1 publications found

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:

ENSG00000298977 (HGNC:):

ENSG00000298977 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05413544).

BS2

High AC in GnomAd4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145805.3. 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
	ISL2	NM_145805.3	MANE Select	c.436C>G	p.Leu146Val	missense	Exon 3 of 6	NP_665804.1	Q96A47

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISL2	ENST00000290759.9	TSL:1 MANE Select	c.436C>G	p.Leu146Val	missense	Exon 3 of 6	ENSP00000290759.4	Q96A47
ISL2	ENST00000558437.1	TSL:3	n.718C>G		non_coding_transcript_exon	Exon 2 of 2
ISL2	ENST00000558656.1	TSL:5	n.248+472C>G		intron	N/A	ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

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:

0.000480

GnomAD2 exomes

AF:

0.0000237

AC:

AN:

84222

AF XY:

0.0000207

show subpopulations

Gnomad AFR exome

AF:

0.00125

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:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1306424

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

644104

show subpopulations

African (AFR)

AF:

0.000561

AC:

AN:

26758

American (AMR)

AF:

0.00

AC:

AN:

25444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22896

East Asian (EAS)

AF:

0.00

AC:

AN:

27942

South Asian (SAS)

AF:

0.00

AC:

AN:

70700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4182

European-Non Finnish (NFE)

AF:

9.60e-7

AC:

AN:

1041414

Other (OTH)

AF:

0.0000186

AC:

AN:

53870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000132

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74162

show subpopulations

African (AFR)

AF:

0.000459

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67942

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000199

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.13

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.5

PhyloP100

1.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.63

REVEL

Benign

0.23

Sift

Benign

0.34

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.23

MutPred

0.53

Gain of catalytic residue at L146 (P = 0.1429)

MVP

0.91

MPC

0.75

ClinPred

0.025

GERP RS

1.6

Varity_R

0.069

gMVP

0.49

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over