rs145221041

Variant names:

• chr15-76338340-G-C
• rs145221041
• NM_145805.3:c.337G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-76338340-G-C
• chr15-76338340-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_145805.3(ISL2):​c.337G>C​(p.Glu113Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,573,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ISL2 NM_145805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 18 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.337G>C	p.Glu113Gln	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.337G>C	p.Glu113Gln	missense	Exon 3 of 6	ENSP00000290759.4	Q96A47
	ISL2	ENST00000558437.1	TSL:3	n.619G>C		non_coding_transcript_exon	Exon 2 of 2
	ISL2	ENST00000558656.1	TSL:5	n.248+373G>C		intron	N/A	ENSP00000453837.1	H0YN25

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152154 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000664 AC: 13 AN: 195880 AF XY: 0.0000919

Gnomad AFR exome AF: 0.000104

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 210 AN: 1421316 Hom.: 0 Cov.: 30 AF XY: 0.000143 AC XY: 101 AN XY: 706586

African (AFR) AF: 0.0000663 AC: 2 AN: 30178

American (AMR) AF: 0.0000237 AC: 1 AN: 42162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35782

South Asian (SAS) AF: 0.0000364 AC: 3 AN: 82412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.000180 AC: 198 AN: 1098416

Other (OTH) AF: 0.000102 AC: 6 AN: 58992

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152266 Hom.: 0 Cov.: 34 AF XY: 0.0000940 AC XY: 7 AN XY: 74462

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000583 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000333 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3476

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	0.26
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.47
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.26	B
Vest4		0.57
MVP		0.94
MPC		1.0
ClinPred		0.22	T
GERP RS		4.3
Varity_R		0.31
gMVP		0.45
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145221041; hg19: chr15-76630681;