rs572722130

Positions:

• chr19-13209374-C-A
• chr19-13209374-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6464G>T​(p.Arg2155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,389,252 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 2.90

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]

CACNA1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07586345).
• BP6: Variant 19-13209374-C-A is Benign according to our data. Variant chr19-13209374-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289416.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr19-13209374-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000223 (34/152280) while in subpopulation AFR AF= 0.000577 (24/41564). AF 95% confidence interval is 0.000398. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6464G>T	p.Arg2155Leu	missense_variant	45/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6464G>T	p.Arg2155Leu	missense_variant	45/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6482G>T	p.Arg2161Leu	missense_variant	46/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6470G>T	p.Arg2157Leu	missense_variant	45/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6467G>T	p.Arg2156Leu	missense_variant	45/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6467G>T	p.Arg2156Leu	missense_variant	45/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6431G>T	p.Arg2144Leu	missense_variant	44/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6326G>T	p.Arg2109Leu	missense_variant	44/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6467G>T	p.Arg2156Leu	missense_variant	45/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6482G>T	p.Arg2161Leu	missense_variant	46/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6473G>T	p.Arg2158Leu	missense_variant	46/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6470G>T	p.Arg2157Leu	missense_variant	45/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6467G>T	p.Arg2156Leu	missense_variant	45/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6467G>T	p.Arg2156Leu	missense_variant	45/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6431G>T	p.Arg2144Leu	missense_variant	44/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*730G>T		non_coding_transcript_exon_variant	9/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*730G>T		3_prime_UTR_variant	9/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000205 AC: 1 AN: 48850 Hom.: 0 AF XY: 0.0000404 AC XY: 1 AN XY: 24770

Gnomad AFR exome AF: 0.000262

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 61 AN: 1236972 Hom.: 1 Cov.: 32 AF XY: 0.0000553 AC XY: 33 AN XY: 597166

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.0000685

Gnomad4 ASJ exome AF: 0.000233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000160

Gnomad4 OTH exome AF: 0.0000795

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74462

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000159

ExAC AF: 0.00000916 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2017	A variant of uncertain significance has been identified in the CACNA1A gene. The R2156L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2156L variantis observed in 1/1162 (0.09%) alleles from individuals of Ashkenazi Jewish background and 3/12,428 (0.02%) alleles from individuals of African background, including 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016). The R2156L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 08, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2021	Variant summary: CACNA1A c.6467G>T (p.Arg2156Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 150934 control chromosomes, predominantly at a frequency of 0.00058 (i.e. 24/41442 alleles) within the African or African-American subpopulation in the gnomAD v3.1 database. The number of occurrences is higher than expected for a pathogenic variant causing Early Infantile Epileptic Encephalopathy-42 (EE42), which tends to be a high penetrance, early onset disease (OMIM). To our knowledge, no occurrence of c.6467G>T in individuals affected with EE42 and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (1x). One of the ClinVar submitters cited evidence of lack of segregation with disease in a family study (SCV000848682.3) while another ClinVar submitter cited a homozygous occurrence of the variant in one individual undergoing testing (SCV000528812.3). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2021

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. -

CACNA1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

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
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.79	.;D;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.076	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.0	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.1	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.026	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.40
MVP		0.82
MPC		0.33
ClinPred		0.70	D
GERP RS		3.1
Varity_R		0.41
gMVP		0.38

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: rs572722130; hg19: chr19-13320188;