17-50561537-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018896.5(CACNA1G):c.78G>A(p.Ser26=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,538,344 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (14 hom.)
• Consequence: CACNA1G NM_018896.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.60

Genes affected

CACNA1G (HGNC:1394): (calcium voltage-gated channel subunit alpha1 G) Voltage-sensitive calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division, and cell death. This gene encodes a T-type, low-voltage activated calcium channel. The T-type channels generate currents that are both transient, owing to fast inactivation, and tiny, owing to small conductance. T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Many alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2011]

CACNA1G-AS1 (HGNC:27377): (CACNA1G antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 17-50561537-G-A is Benign according to our data. Variant chr17-50561537-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1302298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50561537-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00257 (391/151992) while in subpopulation NFE AF= 0.00361 (245/67902). AF 95% confidence interval is 0.00324. There are 2 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 391 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1G	NM_018896.5	c.78G>A	p.Ser26=	synonymous_variant	1/38	ENST00000359106.10
CACNA1G-AS1	NR_038439.1	n.181+391C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1G	ENST00000359106.10	c.78G>A	p.Ser26=	synonymous_variant	1/38	1	NM_018896.5	A2
CACNA1G-AS1	ENST00000505793.1	n.181+391C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 391 AN: 151872 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00441

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00361

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00239 AC: 321 AN: 134512 Hom.: 1 AF XY: 0.00225 AC XY: 166 AN XY: 73708

Gnomad AFR exome AF: 0.000614

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000265

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00336 AC: 4660 AN: 1386352 Hom.: 14 Cov.: 32 AF XY: 0.00326 AC XY: 2229 AN XY: 684182

Gnomad4 AFR exome AF: 0.000634

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000316

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00366

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00257 AC: 391 AN: 151992 Hom.: 2 Cov.: 31 AF XY: 0.00262 AC XY: 195 AN XY: 74296

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00361

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00291 Hom.: 3

Bravo AF: 0.00203

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA1G-AS1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	6.7
Dann	Benign	0.96

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: rs577987926; hg19: chr17-48638898;