rs77664166

Variant names:

• chr9-138074057-C-T
• rs77664166
• NM_000718.4:c.4848C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000718.4(CACNA1B):​c.4848C>T​(p.Ile1616Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,612,292 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (17 hom.)
• Consequence: CACNA1B NM_000718.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.23
• Publications: 1 publications found

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]

CACNA1B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• complex neurodevelopmental disorder with motor features

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-138074057-C-T is Benign according to our data. Variant chr9-138074057-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 599477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00287 (437/152286) while in subpopulation NFE AF = 0.00453 (308/68018). AF 95% confidence interval is 0.00411. There are 1 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000718.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	NM_000718.4	MANE Select	c.4848C>T	p.Ile1616Ile	synonymous	Exon 34 of 47	NP_000709.1
	CACNA1B	NM_001243812.2		c.4848C>T	p.Ile1616Ile	synonymous	Exon 34 of 47	NP_001230741.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.4848C>T	p.Ile1616Ile	synonymous	Exon 34 of 47	ENSP00000360423.1
	CACNA1B	ENST00000371357.5	TSL:5	c.4845C>T	p.Ile1615Ile	synonymous	Exon 33 of 46	ENSP00000360408.1
	CACNA1B	ENST00000371363.5	TSL:5	c.4842C>T	p.Ile1614Ile	synonymous	Exon 33 of 46	ENSP00000360414.1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152168 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00285 AC: 708 AN: 248764 AF XY: 0.00296

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00475

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00356 AC: 5193 AN: 1460006 Hom.: 17 Cov.: 30 AF XY: 0.00354 AC XY: 2571 AN XY: 726342

African (AFR) AF: 0.000538 AC: 18 AN: 33466

American (AMR) AF: 0.000805 AC: 36 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000997 AC: 86 AN: 86256

European-Finnish (FIN) AF: 0.00266 AC: 139 AN: 52230

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00423 AC: 4696 AN: 1111392

Other (OTH) AF: 0.00265 AC: 160 AN: 60346

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152286 Hom.: 1 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74462

African (AFR) AF: 0.000987 AC: 41 AN: 41558

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00386 Hom.: 2

Bravo AF: 0.00242

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00373

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	CACNA1B-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.9
DANN	Benign	0.80
PhyloP100		-2.2
Mutation Taster		=95/5	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: rs77664166; hg19: chr9-140968509;