chr19-13208879-A-ATGGTGG

Variant names:

• chr19-13208879-A-ATGGTGG
• rs759331923
• NM_001127222.2:c.6651_6656dupCCACCA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001127222.2(CACNA1A):​c.6651_6656dupCCACCA​(p.His2218_His2219dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,454,076 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H2219H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent 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, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 19-13208879-A-ATGGTGG is Benign according to our data. Variant chr19-13208879-A-ATGGTGG is described in ClinVar as [Likely_benign]. Clinvar id is 506403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6651_6656dupCCACCA	p.His2218_His2219dup	disruptive_inframe_insertion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6651_6656dupCCACCA	p.His2218_His2219dup	disruptive_inframe_insertion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6669_6674dupCCACCA	p.His2224_His2225dup	disruptive_inframe_insertion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6657_6662dupCCACCA	p.His2220_His2221dup	disruptive_inframe_insertion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6618_6623dupCCACCA	p.His2207_His2208dup	disruptive_inframe_insertion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6513_6518dupCCACCA	p.His2172_His2173dup	disruptive_inframe_insertion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6669_6674dupCCACCA	p.His2224_His2225dup	disruptive_inframe_insertion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6660_6665dupCCACCA	p.His2221_His2222dup	disruptive_inframe_insertion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6657_6662dupCCACCA	p.His2220_His2221dup	disruptive_inframe_insertion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6618_6623dupCCACCA	p.His2207_His2208dup	disruptive_inframe_insertion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*917_*922dupCCACCA		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.000121 AC: 18 AN: 148640 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000441

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000887 AC: 11 AN: 124082 Hom.: 0 AF XY: 0.0000890 AC XY: 6 AN XY: 67406

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.0000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000969

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 191 AN: 1305436 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 90 AN XY: 645392

Gnomad4 AFR exome AF: 0.0000660

Gnomad4 AMR exome AF: 0.0000873

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000781

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.000257

GnomAD4 genome AF: 0.000121 AC: 18 AN: 148640 Hom.: 1 Cov.: 31 AF XY: 0.0000553 AC XY: 4 AN XY: 72384

Gnomad4 AFR AF: 0.0000492

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000441

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000179

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 05, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Jun 23, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759331923; hg19: chr19-13319693;