11-119206440-G-C

Variant names:

• chr11-119206440-G-C
• rs930860175
• NM_005188.4:c.23G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005188.4(CBL):​c.23G>C​(p.Ser8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 1 publications found

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

CBL Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16483742).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005188.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.23G>C	p.Ser8Thr	missense	Exon 1 of 16	NP_005179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.23G>C	p.Ser8Thr	missense	Exon 1 of 16	ENSP00000264033.3
	CBL	ENST00000634586.1	TSL:5	c.23G>C	p.Ser8Thr	missense	Exon 1 of 18	ENSP00000489218.1
	CBL	ENST00000637974.1	TSL:5	c.17G>C	p.Ser6Thr	missense	Exon 1 of 17	ENSP00000490763.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000523 AC: 1 AN: 191226 AF XY: 0.00000957

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424922 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 2 AN XY: 706154

African (AFR) AF: 0.00 AC: 0 AN: 32938

American (AMR) AF: 0.00 AC: 0 AN: 40068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.00 AC: 0 AN: 38670

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4382

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098662

Other (OTH) AF: 0.00 AC: 0 AN: 59090

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.16
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.15	B
Vest4		0.16
MutPred		0.11		Loss of ubiquitination at K7 (P = 0.1016)
MVP		0.81
MPC		0.83
ClinPred		0.28	T
GERP RS		2.4
PromoterAI		0.044	Neutral
Varity_R		0.17
gMVP		0.21
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs930860175; hg19: chr11-119077150;