Genetic Variant ISL2:p.Glu113Gln (chr15-76338340-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_145805.3(ISL2):c.337G>C(p.Glu113Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,573,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

ISL2
NM_145805.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.54

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 18 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.337G>C	p.Glu113Gln	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.337G>C	p.Glu113Gln	missense	Exon 3 of 6	ENSP00000290759.4	Q96A47
ISL2	ENST00000558437.1	TSL:3	n.619G>C		non_coding_transcript_exon	Exon 2 of 2
ISL2	ENST00000558656.1	TSL:5	n.248+373G>C		intron	N/A	ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000664

AC:

AN:

195880

AF XY:

0.0000919

show subpopulations

Gnomad AFR exome

AF:

0.000104

Gnomad AMR exome

AF:

0.0000329

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000148

AC:

210

AN:

1421316

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

101

AN XY:

706586

show subpopulations

African (AFR)

AF:

0.0000663

AC:

AN:

30178

American (AMR)

AF:

0.0000237

AC:

AN:

42162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

35782

South Asian (SAS)

AF:

0.0000364

AC:

AN:

82412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.000180

AC:

198

AN:

1098416

Other (OTH)

AF:

0.000102

AC:

AN:

58992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000118

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000583

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000333

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

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

0.26

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.070

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.55

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

-0.066

MutationAssessor

Benign

1.5

PhyloP100

5.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.47

Sift

Benign

0.17

Sift4G

Benign

0.22

Polyphen

0.26

Vest4

0.57

MVP

0.94

MPC

1.0

ClinPred

0.22

GERP RS

4.3

Varity_R

0.31

gMVP

0.45

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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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