chr1-181750543-C-T

Variant names:

• chr1-181750543-C-T
• rs704332
• NM_001205293.3:c.3731+56C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001205293.3(CACNA1E):​c.3731+56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,559,130 control chromosomes in the GnomAD database, including 266,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (23717 hom., cov: 33)
  • Exomes 𝑓: 0.59 (242758 hom.)
• Consequence: CACNA1E NM_001205293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18
• Publications: 6 publications found

Genes affected

CACNA1E (HGNC:1392): (calcium voltage-gated channel subunit alpha1 E) Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These 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 the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

CACNA1E Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 69

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-181750543-C-T is Benign according to our data. Variant chr1-181750543-C-T is described in ClinVar as Benign. ClinVar VariationId is 1192685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.3731+56C>T		intron_variant	Intron 26 of 47	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.3731+56C>T		intron_variant	Intron 26 of 47	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.3674+56C>T		intron_variant	Intron 25 of 46	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.3731+56C>T		intron_variant	Intron 26 of 46	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.3674+56C>T		intron_variant	Intron 25 of 45	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84392 AN: 151942 Hom.: 23678 Cov.: 33

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.517

GnomAD4 exome AF: 0.585 AC: 823538 AN: 1407070 Hom.: 242758 AF XY: 0.584 AC XY: 410641 AN XY: 703148

African (AFR) AF: 0.473 AC: 15292 AN: 32344

American (AMR) AF: 0.489 AC: 21695 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 15465 AN: 25766

East Asian (EAS) AF: 0.764 AC: 30097 AN: 39406

South Asian (SAS) AF: 0.526 AC: 44618 AN: 84788

European-Finnish (FIN) AF: 0.602 AC: 31435 AN: 52184

Middle Eastern (MID) AF: 0.506 AC: 2863 AN: 5654

European-Non Finnish (NFE) AF: 0.591 AC: 628329 AN: 1063954

Other (OTH) AF: 0.576 AC: 33744 AN: 58566

GnomAD4 genome AF: 0.556 AC: 84482 AN: 152060 Hom.: 23717 Cov.: 33 AF XY: 0.559 AC XY: 41534 AN XY: 74316

African (AFR) AF: 0.479 AC: 19847 AN: 41458

American (AMR) AF: 0.523 AC: 7992 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2103 AN: 3468

East Asian (EAS) AF: 0.739 AC: 3824 AN: 5172

South Asian (SAS) AF: 0.535 AC: 2573 AN: 4812

European-Finnish (FIN) AF: 0.605 AC: 6391 AN: 10568

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39947 AN: 67990

Other (OTH) AF: 0.521 AC: 1100 AN: 2112

Alfa AF: 0.571 Hom.: 12759

Bravo AF: 0.545

Asia WGS AF: 0.619 AC: 2156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 69 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs704332; hg19: chr1-181719679;