17-39175221-C-T

Position:

• chr17-39175221-C-T

Variant summary

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

The NM_000723.5(CACNB1):​c.1769G>A​(p.Gly590Asp) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNB1 NM_000723.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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]

(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=0.09144774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB1	NM_000723.5	c.1769G>A	p.Gly590Asp	missense_variant	14/14	ENST00000394303.8
LOC105371768	XR_934743.3	n.89+504C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB1	ENST00000394303.8	c.1769G>A	p.Gly590Asp	missense_variant	14/14	1	NM_000723.5	P3
CACNB1	ENST00000539338.6	n.3888G>A		non_coding_transcript_exon_variant	12/12	1
	ENST00000579256.1	n.273+1659C>T		intron_variant, non_coding_transcript_variant		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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.1769G>A (p.G590D) alteration is located in exon 14 (coding exon 14) of the CACNB1 gene. This alteration results from a G to A substitution at nucleotide position 1769, causing the glycine (G) at amino acid position 590 to be replaced by an aspartic acid (D). 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	0.095
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.18
Sift	Benign	0.50	T
Sift4G	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.063
MutPred		0.30		Gain of helix (P = 0.0325);
MVP		0.37
MPC		0.76
ClinPred		0.66	D
GERP RS		5.1
Varity_R		0.20
gMVP		0.24

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: chr17-37331474;