12-120641221-T-G

Position:

• chr12-120641221-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001033677.2(CABP1):​c.536T>G​(p.Leu179Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CABP1 NM_001033677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.761

Genes affected

CABP1 (HGNC:1384): (calcium binding protein 1) Calcium binding proteins are an important component of calcium mediated cellular signal transduction. This gene encodes a protein that belongs to a subfamily of calcium binding proteins which share similarity to calmodulin. The protein encoded by this gene regulates the gating of voltage-gated calcium ion channels. This protein inhibits calcium-dependent inactivation and supports calcium-dependent facilitation of ion channels containing voltage-dependent L-type calcium channel subunit alpha-1C. This protein also regulates calcium-dependent activity of inositol 1,4,5-triphosphate receptors, P/Q-type voltage-gated calcium channels, and transient receptor potential channel TRPC5. This gene is predominantly expressed in retina and brain. Alternative splicing results in multiple transcript variants encoding disinct isoforms. [provided by RefSeq, Jul 2012]

CABP1-DT (HGNC:55491): (CABP1 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3762086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABP1	NM_001033677.2	c.536T>G	p.Leu179Arg	missense_variant	1/6	ENST00000316803.8	NP_001028849.1
CABP1	XM_017020235.2	c.536T>G	p.Leu179Arg	missense_variant	1/6		XP_016875724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABP1	ENST00000316803.8	c.536T>G	p.Leu179Arg	missense_variant	1/6	1	NM_001033677.2	ENSP00000317310
CABP1-DT	ENST00000540369.2	n.129+242A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000713 AC: 78 AN: 1093620 Hom.: 0 Cov.: 32 AF XY: 0.0000632 AC XY: 33 AN XY: 522002

Gnomad4 AFR exome AF: 0.000134

Gnomad4 AMR exome AF: 0.000125

Gnomad4 ASJ exome AF: 0.000790

Gnomad4 EAS exome AF: 0.000199

Gnomad4 SAS exome AF: 0.0000681

Gnomad4 FIN exome AF: 0.000140

Gnomad4 NFE exome AF: 0.0000475

Gnomad4 OTH exome AF: 0.000185

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

Jul 27, 2021

The c.536T>G (p.L179R) alteration is located in exon 1 (coding exon 1) of the CABP1 gene. This alteration results from a T to G substitution at nucleotide position 536, causing the leucine (L) at amino acid position 179 to be replaced by an arginine (R). 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	Benign	0.067
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.44	T
Polyphen		0.98	D
Vest4		0.36
MutPred		0.39		Gain of methylation at L179 (P = 0.0032);
MVP		0.64
MPC		1.6
ClinPred		0.54	D
GERP RS		2.6
Varity_R		0.34
gMVP		0.30

Splicing

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: chr12-121079024;