15-76338448-C-G

Variant names:

• chr15-76338448-C-G
• rs746888111
• NM_145805.3:c.445C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_145805.3(ISL2):​c.445C>G​(p.Arg149Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,284,142 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. 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. R149S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: ISL2 NM_145805.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 publications found

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]

ENSG00000298977 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3612873).
• BS2: High AC in GnomAdExome4 at 9 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.445C>G	p.Arg149Gly	missense	Exon 3 of 6	NP_665804.1	Q96A47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISL2	ENST00000290759.9	TSL:1 MANE Select	c.445C>G	p.Arg149Gly	missense	Exon 3 of 6	ENSP00000290759.4	Q96A47
	ISL2	ENST00000558437.1	TSL:3	n.727C>G		non_coding_transcript_exon	Exon 2 of 2
	ISL2	ENST00000558656.1	TSL:5	n.248+481C>G		intron	N/A	ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000701 AC: 9 AN: 1284142 Hom.: 0 Cov.: 31 AF XY: 0.00000475 AC XY: 3 AN XY: 631982

African (AFR) AF: 0.00 AC: 0 AN: 26178

American (AMR) AF: 0.00 AC: 0 AN: 22198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21892

East Asian (EAS) AF: 0.00 AC: 0 AN: 27466

South Asian (SAS) AF: 0.00 AC: 0 AN: 67102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3966

European-Non Finnish (NFE) AF: 0.00000777 AC: 8 AN: 1030098

Other (OTH) AF: 0.0000189 AC: 1 AN: 52862

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.63	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.23	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.57
MutPred		0.27		Loss of stability (P = 0.0723)
MVP		0.90
MPC		0.94
ClinPred		0.56	D
GERP RS		3.5
Varity_R		0.18
gMVP		0.53
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs746888111; hg19: chr15-76630789;