Genetic Variant ISLR2:p.Ala172Ser (chr15-74133268-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020851.3(ISLR2):c.514G>T(p.Ala172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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)

Consequence

ISLR2
NM_020851.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Variant links:

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]

ISLR2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057290852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISLR2	NM_020851.3 link	c.514G>T	p.Ala172Ser	missense_variant	Exon 3 of 3	ENST00000453268.3	NP_065902.1	Q6UXK2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISLR2	ENST00000453268.3 link	c.514G>T	p.Ala172Ser	missense_variant	Exon 3 of 3	1	NM_020851.3	ENSP00000411834.2		Q6UXK2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

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

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514G>T (p.A172S) alteration is located in exon 4 (coding exon 1) of the ISLR2 gene. This alteration results from a G to T substitution at nucleotide position 514, causing the alanine (A) at amino acid position 172 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.039

T;T;T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.72

.;.;T;.;.

M_CAP

Benign

0.0069

MetaRNN

Benign

0.057

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.67

N;N;N;N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.83

N;N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.88

T;T;T;T;T

Sift4G

Benign

0.88

T;T;T;T;T

Polyphen

0.20

B;B;B;B;B

Vest4

0.040

MutPred

0.53

Gain of disorder (P = 0.0423);Gain of disorder (P = 0.0423);Gain of disorder (P = 0.0423);Gain of disorder (P = 0.0423);Gain of disorder (P = 0.0423);

MVP

0.16

ClinPred

0.59

GERP RS

3.5

Varity_R

0.091

gMVP

0.61

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over