chr22-24050917-T-C

Position:

• chr22-24050917-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_012295.4(CABIN1):​c.749T>C​(p.Leu250Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CABIN1 NM_012295.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

Genes affected

CABIN1 (HGNC:24187): (calcineurin binding protein 1) Calcineurin plays an important role in the T-cell receptor-mediated signal transduction pathway. The protein encoded by this gene binds specifically to the activated form of calcineurin and inhibits calcineurin-mediated signal transduction. The encoded protein is found in the nucleus and contains a leucine zipper domain as well as several PEST motifs, sequences which confer targeted degradation to those proteins which contain them. Alternative splicing results in multiple transcript variants encoding two different isoforms. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CABIN1. . Gene score misZ 1.9223 (greater than the threshold 3.09). Trascript score misZ 3.5534 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABIN1	NM_012295.4	c.749T>C	p.Leu250Pro	missense_variant	8/37	ENST00000263119.10	NP_036427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABIN1	ENST00000263119.10	c.749T>C	p.Leu250Pro	missense_variant	8/37	1	NM_012295.4	ENSP00000263119.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.749T>C (p.L250P) alteration is located in exon 8 (coding exon 7) of the CABIN1 gene. This alteration results from a T to C substitution at nucleotide position 749, causing the leucine (L) at amino acid position 250 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	.;M;.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D;N;D;N
REVEL	Uncertain	0.38
Sift	Benign	0.093	T;D;T;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.97, 1.0	.;D;D;D
Vest4		0.92, 0.92
MutPred		0.56		.;Gain of loop (P = 0.0045);.;Gain of loop (P = 0.0045);
MVP		0.82
MPC		1.2
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24447379;