17-39175654-G-T

Variant names:

• chr17-39175654-G-T
• NM_000723.5:c.1336C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000723.5(CACNB1):​c.1336C>A​(p.Pro446Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNB1 NM_000723.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

Genes affected

CACNB1 (HGNC:1401): (calcium voltage-gated channel auxiliary subunit beta 1) The protein encoded by this gene belongs to the calcium channel beta subunit family. It plays an important role in the calcium channel by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

ENSG00000266101 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2144705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB1	NM_000723.5	c.1336C>A	p.Pro446Thr	missense_variant	Exon 14 of 14	ENST00000394303.8	NP_000714.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB1	ENST00000394303.8	c.1336C>A	p.Pro446Thr	missense_variant	Exon 14 of 14	1	NM_000723.5	ENSP00000377840.3
CACNB1	ENST00000539338.6	n.3455C>A		non_coding_transcript_exon_variant	Exon 12 of 12	1
ENSG00000266101	ENST00000579256.1	n.274-1550G>T		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1336C>A (p.P446T) alteration is located in exon 14 (coding exon 14) of the CACNB1 gene. This alteration results from a C to A substitution at nucleotide position 1336, causing the proline (P) at amino acid position 446 to be replaced by a threonine (T). 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	0.099
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.15
Sift	Benign	0.071	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.38		Gain of glycosylation at P446 (P = 0.0491);
MVP		0.59
MPC		0.67
ClinPred		0.46	T
GERP RS		4.0
Varity_R		0.096
gMVP		0.36

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: chr17-37331907;