rs746888111

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-76338448-C-A
• chr15-76338448-C-G
• chr15-76338448-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_145805.3(ISL2):​c.445C>A​(p.Arg149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000627 in 1,435,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ISL2 NM_145805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24173939).
• BS2: High AC in GnomAd4 at 7 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>A	p.Arg149Ser	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>A	p.Arg149Ser	missense	Exon 3 of 6	ENSP00000290759.4	Q96A47
	ISL2	ENST00000558437.1	TSL:3	n.727C>A		non_coding_transcript_exon	Exon 2 of 2
	ISL2	ENST00000558656.1	TSL:5	n.248+481C>A		intron	N/A	ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151794 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 67106 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1284140 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 631980

African (AFR) AF: 0.0000764 AC: 2 AN: 26178

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21890

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: 0.00 AC: 0 AN: 1030098

Other (OTH) AF: 0.00 AC: 0 AN: 52862

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151794 Hom.: 0 Cov.: 34 AF XY: 0.0000405 AC XY: 3 AN XY: 74156

African (AFR) AF: 0.000169 AC: 7 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.35
Sift	Benign	0.50	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.52
MutPred		0.23		Gain of glycosylation at R149 (P = 0.0207)
MVP		0.87
MPC		0.84
ClinPred		0.73	D
GERP RS		3.5
Varity_R		0.18
gMVP		0.56

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;