X-104658929-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017416.2(IL1RAPL2):c.16C>T(p.Leu6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,203,410 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 147 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 9 hem., cov: 24)
  • Exomes 𝑓: 0.00038 (0 hom. 138 hem.)
• Consequence: IL1RAPL2 NM_017416.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.88

Genes affected

IL1RAPL2 (HGNC:5997): (interleukin 1 receptor accessory protein like 2) The protein encoded by this gene is a member of the interleukin 1 receptor family. This protein is similar to the interleukin 1 accessory proteins, and is most closely related to interleukin 1 receptor accessory protein-like 1 (IL1RAPL1). This gene and IL1RAPL1 are located at a region on chromosome X that is associated with X-linked non-syndromic cognitive disability. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075190067).
• BP6: Variant X-104658929-C-T is Benign according to our data. Variant chrX-104658929-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2208312.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chrX-104658929-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RAPL2	NM_017416.2	c.16C>T	p.Leu6Phe	missense_variant	2/11	ENST00000372582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RAPL2	ENST00000372582.6	c.16C>T	p.Leu6Phe	missense_variant	2/11	1	NM_017416.2	P1

Frequencies

GnomAD3 genomes AF: 0.000403 AC: 45 AN: 111766 Hom.: 0 Cov.: 24 AF XY: 0.000265 AC XY: 9 AN XY: 33978

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.0235

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: 0.00420

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.000665

GnomAD3 exomes AF: 0.000337 AC: 60 AN: 178003 Hom.: 0 AF XY: 0.000397 AC XY: 25 AN XY: 62965

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000696

Gnomad OTH exome AF: 0.000454

GnomAD4 exome AF: 0.000376 AC: 410 AN: 1091644 Hom.: 0 Cov.: 28 AF XY: 0.000386 AC XY: 138 AN XY: 357704

Gnomad4 AFR exome AF: 0.0000382

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000753

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.000437

Gnomad4 OTH exome AF: 0.000567

GnomAD4 genome AF: 0.000403 AC: 45 AN: 111766 Hom.: 0 Cov.: 24 AF XY: 0.000265 AC XY: 9 AN XY: 33978

Gnomad4 AFR AF: 0.000163

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: 0.000414

Gnomad4 OTH AF: 0.000665

Alfa AF: 0.000492 Hom.: 17

Bravo AF: 0.000438

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000437 AC: 53

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.16C>T (p.L6F) alteration is located in exon 2 (coding exon 1) of the IL1RAPL2 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the leucine (L) at amino acid position 6 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

IL1RAPL2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	16
Dann	Benign	0.40
DEOGEN2	Benign	0.033	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.080
Sift	Benign	0.63	T
Sift4G	Benign	0.71	T
Polyphen		0.0010	B
Vest4		0.080
MVP		0.39
MPC		1.1
ClinPred		0.027	T
GERP RS		2.5
Varity_R		0.073
gMVP		0.69

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: rs148390300; hg19: chrX-103903610; COSMIC: COSV104656903;