9-137877951-C-T

Variant names:

• chr9-137877951-C-T
• rs757235316
• NM_000718.4:c.18C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000718.4(CACNA1B):​c.18C>T​(p.Asp6Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 148,052 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.732

Genes affected

CACNA1B (HGNC:1389): (calcium voltage-gated channel subunit alpha1 B) The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ENSG00000203987 (HGNC:58213):

LOC100133077 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 9-137877951-C-T is Benign according to our data. Variant chr9-137877951-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1321510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137877951-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.732 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00278 (411/148052) while in subpopulation NFE AF= 0.00408 (271/66490). AF 95% confidence interval is 0.00368. There are 1 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 411 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 1 of 47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 1 of 47		NP_001230741.1
LOC100133077	NR_121583.1	n.2692-2271G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 1 of 47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 1 of 46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 1 of 46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 1 of 47	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 411 AN: 147952 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00205

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00408

Gnomad OTH AF: 0.00442

GnomAD3 exomes AF: 0.00416 AC: 19 AN: 4564 Hom.: 0 AF XY: 0.00426 AC XY: 10 AN XY: 2348

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00237 AC: 2201 AN: 929218 Hom.: 0 Cov.: 19 AF XY: 0.00236 AC XY: 1029 AN XY: 436632

Gnomad4 AFR exome AF: 0.000502

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00185

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.00501

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00278 AC: 411 AN: 148052 Hom.: 1 Cov.: 33 AF XY: 0.00288 AC XY: 208 AN XY: 72166

Gnomad4 AFR AF: 0.000488

Gnomad4 AMR AF: 0.00241

Gnomad4 ASJ AF: 0.00205

Gnomad4 EAS AF: 0.000200

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.00583

Gnomad4 NFE AF: 0.00408

Gnomad4 OTH AF: 0.00436

Alfa AF: 0.00282 Hom.: 0

Bravo AF: 0.00247

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1B: BP4, BP7 -

CACNA1B-related disorder Benign:1

Mar 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.97

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: rs757235316; hg19: chr9-140772403; COSMIC: COSV53132048; COSMIC: COSV53132048;