15-74133089-C-G

Variant names:

• chr15-74133089-C-G
• rs2072464866
• NM_020851.3:c.335C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020851.3(ISLR2):​c.335C>G​(p.Ser112Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ISLR2 NM_020851.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISLR2	NM_020851.3	c.335C>G	p.Ser112Cys	missense_variant	Exon 3 of 3	ENST00000453268.3	NP_065902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISLR2	ENST00000453268.3	c.335C>G	p.Ser112Cys	missense_variant	Exon 3 of 3	1	NM_020851.3	ENSP00000411834.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460552 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726690

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335C>G (p.S112C) alteration is located in exon 4 (coding exon 1) of the ISLR2 gene. This alteration results from a C to G substitution at nucleotide position 335, causing the serine (S) at amino acid position 112 to be replaced by a cysteine (C). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;.;T;T;.;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	.;.;D;D;.;T;D;.
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	2.9	M;M;.;M;M;.;.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.088	T;T;T;T;T;D;T;T
Sift4G	Benign	0.082	T;T;T;T;T;T;T;T
Polyphen		0.70	P;P;.;P;P;.;.;P
Vest4		0.32
MutPred		0.48		Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);Gain of catalytic residue at S112 (P = 0.0312);
MVP		0.70
ClinPred		0.78	D
GERP RS		3.6
Varity_R		0.11
gMVP		0.95

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

Other links and lift over

dbSNP: rs2072464866; hg19: chr15-74425430;