NM_145805.3:c.496G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145805.3(ISL2):​c.496G>C​(p.Gly166Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000859 in 1,164,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

ISL2
NM_145805.3 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.363
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13737163).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ISL2NM_145805.3 linkc.496G>C p.Gly166Arg missense_variant Exon 3 of 6 ENST00000290759.9 NP_665804.1 Q96A47

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ISL2ENST00000290759.9 linkc.496G>C p.Gly166Arg missense_variant Exon 3 of 6 1 NM_145805.3 ENSP00000290759.4 Q96A47
ISL2ENST00000558437.1 linkn.778G>C non_coding_transcript_exon_variant Exon 2 of 2 3
ISL2ENST00000558656.1 linkn.248+532G>C intron_variant Intron 2 of 4 5 ENSP00000453837.1 H0YN25

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000102
AC:
1
AN:
98242
Hom.:
0
AF XY:
0.0000179
AC XY:
1
AN XY:
55732
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
8.59e-7
AC:
1
AN:
1164454
Hom.:
0
Cov.:
30
AF XY:
0.00000177
AC XY:
1
AN XY:
564508
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000103
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 24, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.496G>C (p.G166R) 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 496, causing the glycine (G) at amino acid position 166 to be replaced by an arginine (R). 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
0.26
BayesDel_addAF
Benign
-0.085
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.73
T
M_CAP
Benign
0.073
D
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-0.50
T
MutationAssessor
Benign
0.55
N
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.15
Sift
Benign
0.049
D
Sift4G
Benign
0.37
T
Polyphen
0.0
B
Vest4
0.17
MutPred
0.30
Gain of catalytic residue at G166 (P = 0.0553);
MVP
0.88
MPC
0.88
ClinPred
0.095
T
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.14
gMVP
0.37

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.

Other links and lift over

dbSNP: rs762299691; hg19: chr15-76630840; API