chr22-24038422-A-C

Position:

• chr22-24038422-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_012295.4(CABIN1):​c.171A>C​(p.Lys57Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CABIN1 NM_012295.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0440

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2185596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABIN1	NM_012295.4	c.171A>C	p.Lys57Asn	missense_variant	4/37	ENST00000263119.10	NP_036427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABIN1	ENST00000263119.10	c.171A>C	p.Lys57Asn	missense_variant	4/37	1	NM_012295.4	ENSP00000263119.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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 20, 2024

The c.171A>C (p.K57N) alteration is located in exon 4 (coding exon 3) of the CABIN1 gene. This alteration results from a A to C substitution at nucleotide position 171, causing the lysine (K) at amino acid position 57 to be replaced by an asparagine (N). 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	0.57
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;T;T;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.4	.;L;.;L;.;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D;N;.;N;D;N
REVEL	Benign	0.077
Sift	Benign	0.16	T;T;.;T;T;T
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.085, 0.98	.;B;.;.;D;B
Vest4		0.44, 0.44, 0.47, 0.43
MutPred		0.21		Loss of ubiquitination at K57 (P = 0.0081);Loss of ubiquitination at K57 (P = 0.0081);Loss of ubiquitination at K57 (P = 0.0081);Loss of ubiquitination at K57 (P = 0.0081);Loss of ubiquitination at K57 (P = 0.0081);Loss of ubiquitination at K57 (P = 0.0081);
MVP		0.76
MPC		0.65
ClinPred		0.96	D
GERP RS		0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.56

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: rs1054800571; hg19: chr22-24434870;