15-76337796-T-C

Variant names:

• chr15-76337796-T-C
• NM_145805.3:c.77T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145805.3(ISL2):​c.77T>C​(p.Met26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ISL2 NM_145805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33365163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISL2	NM_145805.3	c.77T>C	p.Met26Thr	missense_variant	Exon 2 of 6	ENST00000290759.9	NP_665804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISL2	ENST00000290759.9	c.77T>C	p.Met26Thr	missense_variant	Exon 2 of 6	1	NM_145805.3	ENSP00000290759.4
ISL2	ENST00000558437.1	n.359T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3
ISL2	ENST00000558656.1	n.77T>C		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000453837.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449020 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 719304

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

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

May 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77T>C (p.M26T) alteration is located in exon 2 (coding exon 2) of the ISL2 gene. This alteration results from a T to C substitution at nucleotide position 77, causing the methionine (M) at amino acid position 26 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.26	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.025	D
Polyphen		0.18	B
Vest4		0.26
MutPred		0.34		Gain of disorder (P = 0.0637);
MVP		0.89
MPC		0.85
ClinPred		0.61	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-76630137;