15-74133689-C-G

Variant names:

• chr15-74133689-C-G
• rs866080805
• NM_020851.3:c.935C>G

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.935C>G​(p.Thr312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ISLR2 NM_020851.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101
• 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=0.094186425).

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.935C>G	p.Thr312Ser	missense	Exon 3 of 3	NP_065902.1	Q6UXK2
	ISLR2	NM_001130136.1		c.935C>G	p.Thr312Ser	missense	Exon 4 of 4	NP_001123608.1	Q6UXK2
	ISLR2	NM_001130137.1		c.935C>G	p.Thr312Ser	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.935C>G	p.Thr312Ser	missense	Exon 3 of 3	ENSP00000411834.2	Q6UXK2
	ISLR2	ENST00000361742.7	TSL:1	c.935C>G	p.Thr312Ser	missense	Exon 4 of 4	ENSP00000355402.3	Q6UXK2
	ISLR2	ENST00000435464.5	TSL:2	c.935C>G	p.Thr312Ser	missense	Exon 4 of 4	ENSP00000411443.1	Q6UXK2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455296 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723456

African (AFR) AF: 0.0000300 AC: 1 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 43532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39424

South Asian (SAS) AF: 0.00 AC: 0 AN: 85492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109014

Other (OTH) AF: 0.00 AC: 0 AN: 60136

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.082
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.090	N
PhyloP100		0.10
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.049
Sift	Benign	0.33	T
Sift4G	Benign	0.29	T
Polyphen		0.77	P
Vest4		0.072
MutPred		0.23		Loss of phosphorylation at T312 (P = 0.1162)
MVP		0.15
ClinPred		0.39	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.66
Mutation Taster		=92/8	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: rs866080805; hg19: chr15-74426030;