15-74133412-G-T

Variant names:

• chr15-74133412-G-T
• rs1335669164
• NM_020851.3:c.658G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020851.3(ISLR2):​c.658G>T​(p.Val220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. V220M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ISLR2 NM_020851.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 0 publications found

Genes affected

ISLR2 (HGNC:29286): (immunoglobulin superfamily containing leucine rich repeat 2) Predicted to be involved in positive regulation of axon extension. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. Predicted to be active in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07340327).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020851.3. 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
	ISLR2	NM_020851.3	MANE Select	c.658G>T	p.Val220Leu	missense	Exon 3 of 3	NP_065902.1	Q6UXK2
	ISLR2	NM_001130136.1		c.658G>T	p.Val220Leu	missense	Exon 4 of 4	NP_001123608.1	Q6UXK2
	ISLR2	NM_001130137.1		c.658G>T	p.Val220Leu	missense	Exon 4 of 4	NP_001123609.1	Q6UXK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISLR2	ENST00000453268.3	TSL:1 MANE Select	c.658G>T	p.Val220Leu	missense	Exon 3 of 3	ENSP00000411834.2	Q6UXK2
	ISLR2	ENST00000361742.7	TSL:1	c.658G>T	p.Val220Leu	missense	Exon 4 of 4	ENSP00000355402.3	Q6UXK2
	ISLR2	ENST00000435464.5	TSL:2	c.658G>T	p.Val220Leu	missense	Exon 4 of 4	ENSP00000411443.1	Q6UXK2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454800 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724086

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111620

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		-0.030
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.017
Sift	Benign	0.26	T
Sift4G	Benign	0.35	T
Polyphen		0.40	B
Vest4		0.073
MutPred		0.29		Gain of helix (P = 0.1736)
MVP		0.14
ClinPred		0.18	T
GERP RS		2.4
Varity_R		0.057
gMVP		0.38
Mutation Taster		=98/2	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: rs1335669164; hg19: chr15-74425753;