chr15-60423762-T-A

Position:

chr15-60423762-T-A

Variant summary

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

The NM_024611.6(ICE2):c.2821A>T(p.Ile941Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,584,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ICE2
NM_024611.6 missense, splice_region

Scores

Splicing: ADA: 0.0008214

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0870

Variant links:

Genes affected

ICE2 (HGNC:29885): (interactor of little elongation complex ELL subunit 2) This gene encodes a protein component of the little elongation complex (LEC), which plays a role in small nuclear RNA (snRNA) transcription. The LEC regulates snRNA transcription by enhancing both RNA Polymerase II occupancy and transcriptional elongation. The encoded protein and other LEC components have been shown to localize to Cajal bodies, which are sites of ribonucleoprotein (RNP) complex assembly. Pseudogenes of this gene have been identified on chromosomes 3 and 4. [provided by RefSeq, May 2017]

ICE2 links:

Genome browser will be placed here

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=0.010368079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICE2	NM_024611.6 linkuse as main transcript	c.2821A>T	p.Ile941Phe	missense_variant, splice_region_variant	16/16	ENST00000261520.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICE2	ENST00000261520.9 linkuse as main transcript	c.2821A>T	p.Ile941Phe	missense_variant, splice_region_variant	16/16	1	NM_024611.6	P1	Q659A1-1
ICE2	ENST00000558121.5 linkuse as main transcript	n.1052A>T		splice_region_variant, non_coding_transcript_exon_variant	5/5	1
ICE2	ENST00000558181.5 linkuse as main transcript	c.*2439A>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	16/16	1			Q659A1-2
ICE2	ENST00000561124.1 linkuse as main transcript	n.434A>T		splice_region_variant, non_coding_transcript_exon_variant	5/5	4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000576

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

GnomAD3 exomes

AF:

0.0000772

AC:

AN:

220198

Hom.:

AF XY:

0.0000756

AC XY:

AN XY:

119070

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00101

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1432130

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

711760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000407

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000576

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.2821A>T (p.I941F) alteration is located in exon 16 (coding exon 15) of the ICE2 gene. This alteration results from a A to T substitution at nucleotide position 2821, causing the isoleucine (I) at amino acid position 941 to be replaced by a phenylalanine (F). 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

0.075

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.11

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.64

M_CAP

Benign

0.0088

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.38

REVEL

Benign

0.061

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.027

Polyphen

0.090

Vest4

0.039

MutPred

0.14

Loss of catalytic residue at I941 (P = 0.02);

MVP

0.19

MPC

0.034

ClinPred

0.085

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00082

dbscSNV1_RF

Benign

0.062

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: 0

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