dbSNP rs752420241: ISL2:p.Leu146Met (chr15-76338439-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145805.3(ISL2):c.436C>A(p.Leu146Met) variant causes a missense 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L146V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ISL2
NM_145805.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.38

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27133715).

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>A	p.Leu146Met	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>A	p.Leu146Met	missense	Exon 3 of 6	ENSP00000290759.4	Q96A47
ISL2	ENST00000558437.1	TSL:3	n.718C>A		non_coding_transcript_exon	Exon 2 of 2
ISL2	ENST00000558656.1	TSL:5	n.248+472C>A		intron	N/A	ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1306424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

644104

African (AFR)

AF:

0.00

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:

0.00

AC:

AN:

1041414

Other (OTH)

AF:

0.00

AC:

AN:

53870

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.0

PhyloP100

1.4

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.11

REVEL

Benign

0.25

Sift

Benign

0.053

Sift4G

Benign

0.16

Polyphen

0.013

Vest4

0.29

MutPred

0.51

Gain of loop (P = 0.3485)

MVP

0.86

MPC

0.77

ClinPred

0.75

GERP RS

1.6

Varity_R

0.11

gMVP

0.38

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over