NM_145805.3:c.521C>A

Variant names:

• chr15-76340285-C-A
• rs371415237
• NM_145805.3:c.521C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145805.3(ISL2):​c.521C>A​(p.Ser174*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ISL2 NM_145805.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34
• 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]

ENSG00000259514 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.521C>A	p.Ser174*	stop_gained	Exon 4 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.521C>A	p.Ser174*	stop_gained	Exon 4 of 6	ENSP00000290759.4	Q96A47
	ISL2	ENST00000558656.1	TSL:5	n.258C>A		non_coding_transcript_exon	Exon 3 of 5	ENSP00000453837.1	H0YN25
	ENSG00000259514	ENST00000559539.1	TSL:3	n.380G>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450402 Hom.: 0 Cov.: 41 AF XY: 0.00000277 AC XY: 2 AN XY: 720966

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 85390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4218

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108234

Other (OTH) AF: 0.00 AC: 0 AN: 59826

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.3
Vest4		0.78
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371415237; hg19: chr15-76632626;