15-60428620-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024611.6(ICE2):c.2629T>G(p.Ser877Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,614,188 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (13 hom.)
• Consequence: ICE2 NM_024611.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010166764).
• BP6: Variant 15-60428620-A-C is Benign according to our data. Variant chr15-60428620-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2645384.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-60428620-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00103 (1505/1461840) while in subpopulation MID AF= 0.0227 (131/5768). AF 95% confidence interval is 0.0195. There are 13 homozygotes in gnomad4_exome. There are 833 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ICE2	NM_024611.6	c.2629T>G	p.Ser877Ala	missense_variant	15/16	ENST00000261520.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ICE2	ENST00000261520.9	c.2629T>G	p.Ser877Ala	missense_variant	15/16	1	NM_024611.6	P1
ICE2	ENST00000558121.5	n.860T>G		non_coding_transcript_exon_variant	4/5	1
ICE2	ENST00000558181.5	c.*2247T>G		3_prime_UTR_variant, NMD_transcript_variant	15/16	1
ICE2	ENST00000561124.1	n.242T>G		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152230 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00146 AC: 368 AN: 251356 Hom.: 4 AF XY: 0.00167 AC XY: 227 AN XY: 135852

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00103 AC: 1505 AN: 1461840 Hom.: 13 Cov.: 31 AF XY: 0.00115 AC XY: 833 AN XY: 727212

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000612

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00142 AC: 217 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74502

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0233 Hom.: 2351

Bravo AF: 0.00151

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00213

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

ICE2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.18
Sift	Benign	0.14	T
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.44
MVP		0.60
MPC		0.21
ClinPred		0.035	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs117095293; hg19: chr15-60720819;