22-20933820-T-G

Position:

• chr22-20933820-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000354336.8(CRKL):​c.353T>G​(p.Leu118Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRKL ENST00000354336.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.46

Genes affected

CRKL (HGNC:2363): (CRK like proto-oncogene, adaptor protein) This gene encodes a protein kinase containing SH2 and SH3 (src homology) domains which has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase, plays a role in fibroblast transformation by BCR-ABL, and may be oncogenic.[provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23221865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRKL	NM_005207.4	c.353T>G	p.Leu118Arg	missense_variant	2/3	ENST00000354336.8	NP_005198.1
CRKL	NR_156180.2	n.881T>G		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRKL	ENST00000354336.8	c.353T>G	p.Leu118Arg	missense_variant	2/3	1	NM_005207.4	ENSP00000346300	P1
CRKL	ENST00000411769.1	c.353T>G	p.Leu118Arg	missense_variant, NMD_transcript_variant	2/4	1		ENSP00000396646

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CRKL-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

The CRKL c.353T>G variant is predicted to result in the amino acid substitution p.Leu118Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.00011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.10
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.87	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.31	T
Sift4G	Benign	0.23	T
Polyphen		0.019	B
Vest4		0.34
MutPred		0.38		Loss of stability (P = 0.0404);
MVP		0.75
MPC		1.4
ClinPred		0.63	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.40

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: rs1921553475; hg19: chr22-21288108; COSMIC: COSV62884145;