chr22-24096051-G-A

Variant names:

• chr22-24096051-G-A
• rs193920999
• NM_012295.4:c.3907G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012295.4(CABIN1):​c.3907G>A​(p.Glu1303Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CABIN1 NM_012295.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.51
• Publications: 3 publications found

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]

CABIN1 Gene-Disease associations (from GenCC):

• neurofibromatosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 99 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012295.4. 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
	CABIN1	NM_012295.4	MANE Select	c.3907G>A	p.Glu1303Lys	missense	Exon 25 of 37	NP_036427.1	Q9Y6J0-1
	CABIN1	NM_001199281.1		c.3907G>A	p.Glu1303Lys	missense	Exon 25 of 37	NP_001186210.1	Q9Y6J0-1
	CABIN1	NM_001201429.2		c.3757G>A	p.Glu1253Lys	missense	Exon 24 of 36	NP_001188358.1	A0A087WWW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABIN1	ENST00000263119.10	TSL:1 MANE Select	c.3907G>A	p.Glu1303Lys	missense	Exon 25 of 37	ENSP00000263119.5	Q9Y6J0-1
	CABIN1	ENST00000398319.6	TSL:1	c.3907G>A	p.Glu1303Lys	missense	Exon 25 of 37	ENSP00000381364.2	Q9Y6J0-1
	CABIN1	ENST00000405822.6	TSL:1	c.3757G>A	p.Glu1253Lys	missense	Exon 24 of 36	ENSP00000384694.2	Q9Y6J0-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251356 AF XY: 0.0000515

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: 0.0000462

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52 AN XY: 727230

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1111988

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.070	T
Sift4G	Benign	0.26	T
Polyphen		0.60	P
Vest4		0.74
MutPred		0.10		Gain of ubiquitination at E1303 (P = 0.0025)
MVP		0.69
MPC		0.35
ClinPred		0.25	T
GERP RS		4.9
Varity_R		0.28
gMVP		0.52
Mutation Taster		=86/14	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: rs193920999; hg19: chr22-24492014; COSMIC: COSV54079534; COSMIC: COSV54079534;