7-107755460-C-T

Variant names:

• chr7-107755460-C-T
• rs1477757302
• NM_024814.4:c.409C>T

Variant summary

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

The NM_024814.4(CBLL1):​c.409C>T​(p.His137Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,586,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CBLL1 NM_024814.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23
• Publications: 0 publications found

Genes affected

CBLL1 (HGNC:21225): (Cbl proto-oncogene like 1) This gene encodes an E3 ubiquitin-ligase for the E-cadherin complex and mediates its ubiquitination, endocytosis, and degradation in the lysosomes. The encoded protein contains a RING-finger domain and is also thought to have a role in control of cell proliferation. A related pseudogene has been identified on chromosome X. Alternative splicing results in a non-coding transcript variant. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024814.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLL1	NM_024814.4	MANE Select	c.409C>T	p.His137Tyr	missense	Exon 5 of 6	NP_079090.2	Q75N03-1
	CBLL1	NM_001284291.2		c.406C>T	p.His136Tyr	missense	Exon 5 of 6	NP_001271220.1	Q75N03-2
	CBLL1	NR_024199.3		n.504C>T		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLL1	ENST00000440859.8	TSL:1 MANE Select	c.409C>T	p.His137Tyr	missense	Exon 5 of 6	ENSP00000401277.2	Q75N03-1
	CBLL1	ENST00000222597.7	TSL:1	c.406C>T	p.His136Tyr	missense	Exon 5 of 6	ENSP00000222597.2	Q75N03-2
	CBLL1	ENST00000698938.1		c.445C>T	p.His149Tyr	missense	Exon 5 of 6	ENSP00000514046.1	A0A8V8TMY5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151502 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434862 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 713862

African (AFR) AF: 0.0000313 AC: 1 AN: 31968

American (AMR) AF: 0.00 AC: 0 AN: 42350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 37998

South Asian (SAS) AF: 0.00 AC: 0 AN: 82542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097340

Other (OTH) AF: 0.00 AC: 0 AN: 59054

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151502 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74008

African (AFR) AF: 0.0000485 AC: 2 AN: 41230

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67850

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.28
Sift	Benign	0.40	T
Sift4G	Benign	0.59	T
Polyphen		0.99	D
Vest4		0.70
MutPred		0.29		Loss of disorder (P = 0.0655)
MVP		0.76
MPC		1.0
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.77
Mutation Taster		=23/77	disease causing

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: rs1477757302; hg19: chr7-107395905;